Letter to the Editor Regarding the Article Rotenone Increases Isoniazid Toxicity but Does Not Cause Significant Liver Injury: Implications for the Hypothesis that Inhibition of the Mitochondrial Electron Transport Chain Is a Common Mechanism of Idiosyncratic Drug-Induced Liver Injury by Cho and Co-Workers, 2019Click to copy article linkArticle link copied!
- Bernard FromentyBernard FromentyINSERM, Université de Rennes, INRAE, Nutrition, Metabolisms, and Cancer (NuMeCan) Institut, UMR_A 1341, UMR_S 1241, F-35000 Rennes, FranceMore by Bernard Fromenty
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Dear Editor, Idiosyncratic drug-induced liver injury (iDILI) is a major issue for the treated patients because of its unpredictability and its potential severity. It is also a concern for the pharmaceutical companies since severe or lethal liver injury can lead to the withdrawal of drugs from the market, or earlier during clinical trials, thus causing significant financial losses. (1) While immune response plays a major role, (2) it is now accepted that mitochondrial dysfunction is also an important mechanism whereby drugs can induce iDILI. (1,3,4) The unpredictability of drug-induced mitochondrial dysfunction in iDILI can be due to different causes such as drug–drug pharmacokinetic and/or pharmacodynamic interactions, the presence of an underlying liver disease, or different types of genetic predisposition affecting mitochondrial function. (1,5) Genetic defects affecting the mitochondrial electron transport chain (mtETC) or the mitochondrial fatty acid oxidation (mtFAO) pathway have been reported to favor mitochondrial dysfunction and liver injury induced by several drugs such as the anticonvulsant drug valproic acid and some antiretroviral agents. (1,5)
In a recent article published in Chemical Research in Toxicology, Cho and co-workers treated C57BL/6 mice with rotenone (a prototypical inhibitor of the mitochondrial respiratory chain (MRC) complex I), isoniazid (an antituberculosis drug inhibiting the MRC complex II), or both compounds, over a 6-week period. (6) Whereas treatment with rotenone alone (0.05 or 0.1% w/w in food) or isoniazid alone (0.2% w/w in food) did not cause death among the animals, the co-administration of rotenone and isoniazid led to lethality in 100% of the mice. This toxicity was not related to liver injury as assessed by hepatic histology and serum glutamate dehydrogenase (GLDH) activity. Notably, the latter investigations were performed after only 3 and 6 days since the co-treated mice did not survive afterward. From these results, the authors conclude that inhibition of the mtETC is not a significant mechanism of iDILI. (6) Although this in vivo study provides interesting data, this conclusion is somewhat misleading for the following reasons. First and foremost, there is already strong evidence that mtETC impairment is responsible for liver injury with different drugs, especially with drugs altering the replication or translation of mitochondrial DNA (mtDNA), which encodes for 13 mtETC polypeptides. Of note, such alteration eventually leads to an impairment of electron transfer from both complexes I and II and onward of the hepatic mtETC. For instance, phase II clinical trials with the anti-HBV drug fialuridine, which inhibits mtDNA replication, (7) were prematurely interrupted due to serious adverse effects including unmanageable lactic acidosis, microvesicular steatosis, and liver failure requiring liver transplantation, or even leading to death. (8,9) Similar adverse effects can be induced by different antiretroviral nucleoside reverse-transcriptase inhibitors (NRTIs) such as zalcitabine (ddC), stavudine (d4T), and didanosine (ddI), (10,11) which also strongly inhibit mtDNA replication. (7,10) Experimental investigations with fialuridine and NRTIs demonstrated the major role of mtDNA depletion and mtETC impairment in the development of liver injury. (10,12,13) NRTI-induced hepatotoxicity occurs only in some patients, thus suggesting the role of underlying factors such as genetic predisposition. (5,14) Furthermore, other experimental investigations support the role of mtETC impairment in liver injury induced by amiodarone, (15,16) perhexiline, (17) and buprenorphine. (18)
Second, in the study of Cho and colleagues, the premature death from extra-hepatic causes of the mice co-treated with rotenone and isoniazid most probably precluded the possibility to observe delayed mitochondrial toxicity in liver and subsequent hepatic injury. (6) Notably, liver is not the primary target organ during rotenone toxicity. (19) Human and animals studies showed that rotenone-induced mitochondrial toxicity causes respiratory depression, cardiovascular collapse, and severe metabolic (i.e., lactic) acidosis. (19) In addition to heart and lungs, kidneys and spleen are also damaged after rotenone exposure. (20) Regarding isoniazid, although hepatotoxicity is a significant adverse event in treated patients, hypotension, renal failure, and metabolic acidosis could also occur. (21,22) A thorough necropsy of the deceased mice might have uncovered which vital organs were severely damaged by rotenone. Moreover, in vitro investigations in hepatocytes might have permitted to evaluate the toxicity of rotenone, isoniazid, and their combination. Indeed, previous investigations reported that rotenone and isoniazid could induce toxicity in hepatic cells. (23,24)
Third, the authors looked for hepatic injury in liver sections by using hematoxylin and eosin staining. However, this staining method is not appropriate in order to detect microvesicular steatosis, (25) a liver lesion commonly occurring with drugs and toxins inducing mitochondrial dysfunction. (7,26) Regardless of the pathophysiological context, minor or moderate microvesicular steatosis is better detected with Oil red O or Sudan III staining on frozen liver sections. (25,27)
Investigations in animals are useful in order to study DILI including iDILI, but different factors may greatly modulate the severity of liver injury such as drug distribution and metabolism as well as animal species and strain. (1,28,29) Interestingly, isoniazid did not induce microvesicular steatosis in C57BL/6J mice, whereas this liver lesion was observed in other strains such as BALB/cJ, DBA/2J, and LG/J mice. (30) The latter study and others (1,14,31,32) underline the importance of genetic susceptibility in the occurrence of drug-induced liver injury, in particular when considering genes encoding for mitochondrial proteins. Importantly, drug-induced mtETC toxicity can cause not only microvesicular steatosis and cell death but also other liver lesions such as steatohepatitis and cholestasis. (5,17,33) Hence, more investigations are clearly needed in order to identify the main factors able to modulate drug-induced mitochondrial dysfunction in liver. While in vivo investigations may better reflect the complexity of iDILI, complementary in vitro experiments are also useful to decipher the mechanisms whereby drugs can be toxic for mitochondria.
Acknowledgments
I am very grateful to Dr Julie Massart for her critical reading of this letter.
References
This article references 33 other publications.
- 1Labbe, G., Pessayre, D., and Fromenty, B. (2008) Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335– 353, DOI: 10.1111/j.1472-8206.2008.00608.xGoogle Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptlaltr0%253D&md5=a60eddefd1f7444b9494e4981333f3b8Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studiesLabbe, Gilles; Pessayre, Dominique; Fromenty, BernardFundamental & Clinical Pharmacology (2008), 22 (4), 335-353CODEN: FCPHEZ; ISSN:0767-3981. (Wiley-Blackwell)A review. Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects such as lactic acidosis and rhabdomyolysis in some patients. By severely altering mitochondrial function in the liver, drugs can induce microvesicular steatosis, a potentially severe lesion that can be assocd. with profound hypoglycemia and encephalopathy. They can also trigger hepatic necrosis and/or apoptosis, causing cytolytic hepatitis, which can evolve into liver failure. Milder mitochondrial dysfunction, sometimes combined with an inhibition of triglyceride egress from the liver, can induce macrovacuolar steatosis, a benign lesion in the short term. However, in the long term this lesion can evolve in some individuals towards steatohepatitis, which itself can progress to extensive fibrosis and cirrhosis. As liver injury caused by mitochondrial dysfunction can induce the premature end of clin. trials, or drug withdrawal after marketing, it should be detected during the preclin. safety studies. Several in vitro and in vivo investigations can be performed to det. if newly developed drugs disturb mitochondrial fatty acid oxidn. (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition (MPT) pore. As drugs can be deleterious for hepatic mitochondria in some individuals but not in others, it may also be important to use novel animal models with underlying mitochondrial and/or metabolic abnormalities. This could help us to better predict idiosyncratic liver injury caused by drug-induced mitochondrial dysfunction.
- 2Cho, T. and Uetrecht, J. (2017) How reactive metabolites induce an immune response that sometimes leads to an idiosyncratic drug reaction. Chem. Res. Toxicol. 30, 295– 314, DOI: 10.1021/acs.chemrestox.6b00357Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslagsb3M&md5=04137ee96f32fea06c39a22eea4e4200How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug ReactionCho, Tiffany; Uetrecht, JackChemical Research in Toxicology (2017), 30 (1), 295-314CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addn., evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-assocd. mol. pattern mols. that activate antigen presenting cells. Both are required for an immune response. In addn., drugs may induce an immune response through inflammasome activation. The authors have found examples in which the ability to activate inflammasomes differentiated drugs that cause IDRs from similar drugs that do not. There are other hypotheses that do not involve an immune mechanism such as mitochondrial injury and bile salt export pump (BSEP) inhibition. With some possible exception, these hypotheses are unlikely to be able to completely explain IDRs. However, some types of mitochondrial injury or BSEP inhibition could produce danger signals. The major mechanism that protects individuals from IDRs appears to be immune tolerance. Consistent with this hypothesis, the authors used checkpoint inhibition to develop the first animal model of idiosyncratic drug-induced liver injury that has the same characteristics as the idiosyncratic injury in humans. This was accomplished by treating Pd-1-/- mice with anti-CTLA-4 antibodies and amodiaquine. The combination of the Pd-1-/- mouse and anti-CTLA-4 also unmasks the ability of other drugs such as isoniazid to cause delayed type liver injury. This model should allow rigorous testing of mechanistic hypotheses that was impossible in the past.
- 3Porceddu, M., Buron, N., Roussel, C., Labbe, G., Fromenty, B., and Borgne-Sanchez, A. (2012) Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria. Toxicol. Sci. 129, 332– 345, DOI: 10.1093/toxsci/KFS197Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVSmsrnP&md5=55bab720ede256a4dc3cb9d4f5283954Prediction of Liver Injury Induced by Chemicals in Human With a Multiparametric Assay on Isolated Mouse Liver MitochondriaPorceddu, Mathieu; Buron, Nelly; Roussel, Celestin; Labbe, Gilles; Fromenty, Bernard; Borgne-Sanchez, AnnieToxicological Sciences (2012), 129 (2), 332-345CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)Drug-induced liver injury (DILI) in humans is difficult to predict using classical in vitro cytotoxicity screening and regulatory animal studies. This explains why numerous compds. are stopped during clin. trials or withdrawn from the market due to hepatotoxicity. Thus, it is important to improve early prediction of DILI in human. In this study, we hypothesized that this goal could be achieved by investigating drug-induced mitochondrial dysfunction as this toxic effect is a major mechanism of DILI. To this end, we developed a high-throughput screening platform using isolated mouse liver mitochondria. Our broad spectrum multiparametric assay was designed to detect the global mitochondrial membrane permeabilization (swelling), inner membrane permeabilization (transmembrane potential), outer membrane permeabilization (cytochrome c release), and alteration of mitochondrial respiration driven by succinate or malate/glutamate. A pool of 124 chems. (mainly drugs) was selected, including 87 with documented DILI and 37 without reported clin. hepatotoxicity. Our screening assay revealed an excellent sensitivity for clin. outcome of DILI (94 or 92% depending on cutoff) and a high pos. predictive value (89 or 82%). A highly significant relationship between drug-induced mitochondrial toxicity and DILI occurrence in patients was calcd. (p < 0.001). Moreover, this multiparametric assay allowed identifying several compds. for which mitochondrial toxicity had never been described before and even helped to clarify mechanisms with some drugs already known to be mitochondriotoxic. Investigation of drug-induced loss of mitochondrial integrity and function with this multiparametric assay should be considered for integration into basic screening processes at early stage to select drug candidates with lower risk of DILI in human. This assay is also a valuable tool for assessing the mitochondrial toxicity profile and investigating the mechanism of action of new compds. and marketed compds.
- 4Ramachandran, A., Visschers, R. G., Duan, L., Akakpo, J. Y., and Jaeschke, H. (2018) Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives. J. Clin. Transl. Res. 4, 75– 100, DOI: 10.18053/jctres.04.201801.005Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVCisb7K&md5=1c07c344415a1338ea980d88bf2f50cfMitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectivesRamachandran, Anup; Duan, Luqi; Akakpo, Jephte Y.; Jaeschke, HartmutJournal of Clinical and Translational Research (2018), 4 (1), 75-100CODEN: JCTRGT; ISSN:2424-810X. (Whioce Publishing Pte. Ltd.)Mitochondria are crit. cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metab., as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examd. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clin. useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clin. relevant animal models and more translational studies using mechanistic biomarkers are crit. for progress in this area. Relevance for patients: This review focuses on the role of mitochondrial dysfunction in liver injury mechanisms of clin. important drugs like acetaminophen, diclofenac, rifampicin, isoniazid, amiodarone and others. A better understanding of the mechanisms in animal models and their translation to patients will be crit. for the identification of new therapeutic targets.
- 5Begriche, K., Massart, J., Robin, M. A., Borgne-Sanchez, A., and Fromenty, B. (2011) Drug-induced toxicity on mitochondria and lipid metabolism. Mechanistic diversity and deleterious consequences for the liver. J. Hepatol. 54, 773– 794, DOI: 10.1016/j.jhep.2010.11.006Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjs12hsr8%253D&md5=ff6a28895ffcc230cb438565b164f207Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liverBegriche, Karima; Massart, Julie; Robin, Marie-Anne; Borgne-Sanchez, Annie; Fromenty, BernardJournal of Hepatology (2011), 54 (4), 773-794CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)A review. Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P 450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clin. and pathol. features. Microvesicular steatosis, a potentially severe liver lesion usually assocd. with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidn. (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate redn. of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-assocd. triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overprodn. of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent mol., genetic predispositions (in particular those involving mitochondrial enzymes), alc. intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).
- 6Cho, T., Wang, X., and Uetrecht, J. (2019) Rotenone increases isoniazid toxicity but does not cause significant liver injury: implications for the hypothesis that inhibition of the mitochondrial electron transport chain is a common mechanism of idiosyncratic drug-induced liver injury. Chem. Res. Toxicol. 32, 1423– 1431, DOI: 10.1021/acs.chemrestox.9b00116Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtF2gsb%252FP&md5=b10936e23ac156bc73888f537892ad63Rotenone Increases Isoniazid Toxicity but Does Not Cause Significant Liver Injury: Implications for the Hypothesis that Inhibition of the Mitochondrial Electron Transport Chain Is a Common Mechanism of Idiosyncratic Drug-Induced Liver InjuryCho, Tiffany; Wang, Xijin; Uetrecht, JackChemical Research in Toxicology (2019), 32 (7), 1423-1431CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Idiosyncratic drug reactions (IDRs) significantly increase the risk of failure in drug development. The major IDR leading to drug candidate failure is idiosyncratic drug-induced liver injury (IDILI). Although most evidence suggests that IDRs are mediated by the immune system, there are other hypotheses, such as mitochondrial dysfunction. Many pharmaceutical companies routinely screen for mitochondrial toxicity in an attempt to "derisk" drug candidates. However, the basic hypothesis has never been rigorously tested. A major assay used for this screening involves measurement of inhibition of the mitochondrial electron transport chain. One study found that the combination of rotenone and isoniazid, which inhibit mitochondrial complex I and II, resp., were synergistic in causing hepatocyte toxicity in vitro and suggested the combination of another drug that inhibited complex I would increase the risk of isoniazid-induced liver injury in patients. We tested this hypothesis in vivo where wild-type and PD-1-/- mice administered anti-CTLA-4, our impaired immune tolerance mouse model, were given 0.02% (w/v) rotenone in water or 0.1%, 0.05%, and 0.01% (wt./wt.) rotenone alone or in combination with isoniazid in food. The cotreatment led to lethality in 100% of the animals receiving 0.1% rotenone and 0.2% isoniazid and 83% of the animals cotreated with 0.05% rotenone and 0.2% isoniazid in food. Nevertheless, there was no significant increase in GLDH or histol. evidence of liver injury. No signs of toxicity were obsd. in any of the mice given rotenone or isoniazid alone. Even though inhibition of the mitochondrial electron transport chain did not lead to significant liver toxicity, it could provide danger signals that promote immune-mediated liver injury. However, rotenone did not significantly increase the liver injury induced by isoniazid in our impaired immune tolerance model. Overall, we conclude that inhibition of the mitochondrial electron transport chain is not a significant mechanism of IDILI.
- 7Fromenty, B. and Pessayre, D. (1995) Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101– 154, DOI: 10.1016/0163-7258(95)00012-6Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXnvVKrs78%253D&md5=16297ef1c7df483cd4d6504679fa4671Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicityFromenty, Bernard; Pessayre, DominiquePharmacology & Therapeutics (1995), 67 (1), 101-54CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review with many refs. Severe and prolonged impairment of mitochondrial β-oxidn. leads to microvesicular steatosis, and, in severe forms, to liver failure, coma death. Impairment of mitochondrial β-oxidn. may be either genetic or acquired, and different causes may add their effects to inhibit β-oxidn. severely and trigger the syndrome. Drugs and some endogenous compds. can sequester CoA and/or inhibit mitochondrial β-oxidn. enzymes (aspirin, valproic acid, tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine and tianeptine); they may inhibit both mitochondrial β-oxidn. and oxidative phosphorylation (endogenous bile acids, amiodarone, perhexiline and diethylaminoethoxyhesestrol), or they may impair mitochondrial DNA transcription (interferon-α), or decrease mitochondrial DNA replication (dideoxynucleoside analogs), while other compds. (ethanol, female sex hormones) act through a combination of different mechanisms. Any investigational mol. should be screened for such effects.
- 8McKenzie, R., Fried, M. W., Sallie, R., Conjeevaram, H., Di Bisceglie, A. M., Park, Y., Savarese, B., Kleiner, D., Tsokos, M., Luciano, C. (1995) Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N. Engl. J. Med. 333, 1099– 1105, DOI: 10.1056/NEJM199510263331702Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjvVWg&md5=d91c2cfd5401644b5720395eb30b4144Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analog for chronic hepatitis BMcKenzie, Robin; Fried, Michael W.; Sallie, Richard; Conjeevaram, Hari; Di Bisceglie, Adrian M.; Park, Yoon; Savarese, Barbara; Kleiner, David; Tsokos, Maria; et al.New England Journal of Medicine (1995), 333 (17), 1099-105CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)We describe severe and unexpected multisystem toxicity that occurred during a study of the antiviral nucleoside analog fialuridine (1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil, or FIAU) as therapy for chronic hepatitis B virus infection. Fifteen patients with chronic hepatitis B were randomly assigned to receive fialuridine at a dose of either 0.10 or 0.25 mg per kg of body wt. per day for 24 wk and were monitored every 1 to 2 wk by means of a phys. examn., blood tests, and testing for hepatitis B virus markers. During the 13th week lactic acidosis and liver failure suddenly developed in one patient. The study was terminated on an emergency basis, and all treatment with fialuridine was discontinued. Seven patients were found to have severe hepatotoxicity, with progressive lactic acidosis, worsening jaundice, and deteriorating hepatic synthetic function despite the discontinuation of fialuridine. Three other patients had mild hepatotoxicity. Several patients also had pancreatitis, neuropathy, or myopathy. Of the seven patients with severe hepatotoxicity, five died and two survived after liver transplantation. Histol. anal. of liver tissue revealed marked accumulation of microvesicular and macrovesicular fat, with minimal necrosis of hepatocytes or architectural changes. Electron microscopy showed abnormal mitochondria and the accumulation of fat in hepatocytes. In patients with chronic hepatitis B, treatment with fialuridine induced a severe toxic reaction characterized by hepatic failure, lactic acidosis, pancreatitis, neuropathy, and myopathy. This toxic reaction was probably caused by widespread mitochondrial damage and may occur infrequently with other nucleoside analogs.
- 9Mak, L. Y., Seto, W. K., Lai, C. L., and Yuen, M. F. (2016) DNA polymerase inhibitors for treating hepatitis B: a safety evaluation. Expert Opin. Drug Saf. 15, 383– 392, DOI: 10.1517/14740338.2016.1139573Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitlOrur0%253D&md5=0534d0be3cb9ec93f175893248dea76cDNA polymerase inhibitors for treating hepatitis B: a safety evaluationMak, Lung-Yi; Seto, Wai-Kay; Lai, Ching-Lung; Yuen, Man-FungExpert Opinion on Drug Safety (2016), 15 (3), 383-392CODEN: EODSA9; ISSN:1474-0338. (Taylor & Francis Ltd.)Oral nucleoside/ nucleotide analogs (NAs) are currently the mainstay of treatment for patients with chronic hepatitis B virus (HBV) infection. They are generally safe to use. However, since their approval in the last decade and a half, the literature has reported adverse effects assocd. with the use of NA in HBV patients. A comprehensive review on the drug safety is lacking. Significant adverse effects assocd. with NA use in HBV patients including muscle toxicity, peripheral neuropathy, nephrotoxicity and lactic acidosis are discussed. The reported prevalence of each adverse effect, as well as their predictive factors, reversibility and their use in pregnancy and lactating mothers are covered in this review. Novel data regarding reno-protective effect of telbivudine are also discussed. Use of NA in HBV is generally safe. Uncommon adverse effects can be minimized or detected early if clinicians exercise adequate precautions when using NA for at-risk populations with regular monitoring.
- 10Igoudjil, A., Begriche, K., Pessayre, D., and Fromenty, B. (2006) Mitochondrial, metabolic and genotoxic effects of antiretroviral nucleoside reverse-transcriptase inhibitors. Anti-Infect. Agents Med. Chem. 5, 273– 292, DOI: 10.2174/187152106777697871Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmsVOitbY%253D&md5=ce2be55536e46355e1cf92e7459b7313Mitochondrial, metabolic and genotoxic effects of antiretroviral nucleoside reverse-transcriptase inhibitorsIgoudjil, Anissa; Begriche, Karima; Pessayre, Dominique; Fromenty, BernardAnti-Infective Agents in Medicinal Chemistry (2006), 5 (3), 273-292CODEN: AAMCC2; ISSN:1871-5214. (Bentham Science Publishers Ltd.)A review. Nucleoside reverse-transcriptase inhibitors (NRTIs), including stavudine (d4T), zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC) and abacavir (ABC), inhibit/terminate the reverse transcription of the HIV virus, and markedly improve life expectancy and quality of life in HIV-infected patients. This progress, however, has come at the price of frequent side effects. NRTIs can cause myopathy, cardiomyopathy, pancreatitis, peripheral neuropathy, lipodystrophy, hepatic steatosis, lactic acidosis and/or liver failure. Most of these adverse effects have been ascribed to the inhibition/termination of mitochondrial DNA (mtDNA) replication, thus depleting mtDNA. Among NRTIs, the so-called "D-drugs" (ddC, ddI, d4T) seem to be the most potent inhibitors of mitochondrial DNA polymerase γ and mtDNA replication. MtDNA depletion impairs the synthesis of mtDNA-encoded respiratory chain polypeptides. In turn, the depressed respiratory chain activity can secondarily inhibit fatty acid oxidn. (FAO), pyruvate dehydrogenase and the tricarboxylic acid cycle, thus possibly leading to steatosis and lactic acidosis. The partial block in the flow of electrons also increases the generation of reactive oxygen species (ROS) by overly reduced respiratory chain complexes, and can also lead to cell death. Importantly, both the therapeutic effects of nucleoside analogs and their mtDNA-depleting action require their initial transformation into the triphosphate derivs. This activation pathway competes with conjugation and/or degrdn. pathways. Exogenous and endogenous factors can diversely modulate these anabolic and catabolic pathways, to modulate antiretroviral efficacy and toxicity. Importantly, NRTIs can impair mitochondrial function and cell homeostasis without depleting mtDNA. Possible mechanisms could include the accumulation of oxidative lesions and mutations in mtDNA, drug-induced inhibition of the adenine nucleotide translocator, diverse effects on FAO enzymes and/or cofactors such as L-carnitine, and also genotoxic effects on nDNA. Some of these "mtDNA-unrelated" effects could disturb lipid homeostasis and participate to cell death in some tissues. Although it is still unclear why different nucleoside analogs tend to have different tissue-selective toxicities, and why some individuals may be more susceptible, recent data allow us to put forward some hypotheses.
- 11Wang, Y., Lin, Z., Liu, Z., Harris, S., Kelly, R., Zhang, J., Ge, W., Chen, M., Borlak, J., and Tong, W. (2013) A unifying ontology to integrate histological and clinical observations for drug-induced liver injury. Am. J. Pathol. 182, 1180– 1187, DOI: 10.1016/j.ajpath.2012.12.033Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXksFaksL8%253D&md5=ab75c26b3ae1cb7c4a0f26d9654da2b1A Unifying Ontology to Integrate Histological and Clinical Observations for Drug-Induced Liver InjuryWang, Yuping; Lin, Zhi; Liu, Zhichao; Harris, Stephen; Kelly, Reagan; Zhang, Jie; Ge, Weigong; Chen, Minjun; Borlak, Jurgen; Tong, WeidaAmerican Journal of Pathology (2013), 182 (4), 1180-1187CODEN: AJPAA4; ISSN:0002-9440. (Elsevier B.V.)Drug-induced liver injury (DILI) may present any morphol. characteristic of acute or chronic liver disease with no standardized terminol. in place. Defining lexemes of DILI histopathol. would allow the development of advanced knowledge discovery and data mining tools for across comparisons of publicly available information. For these purposes, a DILI ontol. (DILIo) was developed by using the Unified Medical Language System tool and the standardized terminol. of the Systematized Nomenclature of Medicine-Clin. Terms (SNOMED CT). The DILIo was entrained on findings of 114 US Food and Drug Administration-approved drugs by extg. all clin. DILI-related histopathol. descriptions for 1082 liver biopsy samples, which were then analyzed using the Unified Medical Language System MetaMap and subsequently mapped to the SNOMED CT. The DILIo provides a std. means to describe and organize liver injury induced by drugs, enabling comparative anal. of drugs within and across histopathol. terms. The anal. showed that flutamide, troglitazone, diclofenac, isoniazid, and tamoxifen were reported to have the most diverse histopathol. observations in liver biopsy. Necrosis, cholestasis, fatty degeneration, fibrosis, infiltrate, and hepatic necrosis were the most frequent terms used as descriptors of histopathol. features of DILI. In conclusion, DILIo entrains different algorithms for an efficient meta-anal. of published findings for an improved understanding of mechanisms and clin. characteristics of DILI.
- 12Lewis, W., Griniuviene, B., Tankersley, K. O., Levine, E. S., Montione, R., Engelman, L., de Courten-Myers, G., Ascenzi, M. A., Hornbuckle, W. E., Gerin, J. L., and Tennant, B. C. (1997) Depletion of mitochondrial DNA, destruction of mitochondria, and accumulation of lipid droplets result from fialuridine treatment in woodchucks (Marmota monax). Lab. Invest. 76, 77– 87Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhsVCisr4%253D&md5=9c305de0ca7c11b3aac2dc0a10b6e2ebDepletion of mitochondrial DNA, destruction of mitochondria, and accumulation of lipid droplets result from fialuridine treatment in woodchucks (Marmota monax)Lewis, William; Griniuviene, Brone; Tankersley, Kevin O.; Levine, Eric S.; Montione, Richard; Engelman, Laura; De Courten-Myers, Gabrielle; Ascenzi, Mary A.; Hornbuckle, William E.; et al.Laboratory Investigation (1997), 76 (1), 77-87CODEN: LAINAW; ISSN:0023-6837. (Williams & Wilkins)Fialuridine (FIAU, 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil) is toxic to liver, heart, muscle, and nerve in clin. trials for chronic viral hepatitis (CH). Mitochondrial toxicity was hypothesized. To address pathophysiol. mechanisms, we examd. mitochondrial changes in FIAU-treated woodchucks (WC) with CH from woodchuck hepatitis virus infection. WC (with and without CH from woodchuck hepatitis virus infection) were treated with FIAU (1.5 mg/kg/day) for 12 wk. WC were killed. Liver, heart, skeletal muscle, and kidney samples underwent DNA extn. and were analyzed ultrastructurally (TEM). Myocardium, skeletal muscles, and liver samples were analyzed histol. Abundance of hepatic, myocardial, muscle, and kidney mtDNA decreased in FIAU-treated WC, but the magnitude varied. MtDNA decreased 55% in heart, 65% in kidney, 74% in liver, and 87% in muscle (for each tissue: FIAU-treated vs. FIAU-untreated). Cellular damage was characterized ultrastructurally by mitochondrial enlargement, cristae dissoln., and lipid droplets. Lipid droplets found in the heart, diaphragm, biceps, and liver were sufficient to identify FIAU-treated WC (each). Widespread mitochondrial damage to many tissues resulted from chronic FIAU treatment and occurred irresp. of CH. It manifested with mtDNA depletion, intracytoplasmic lipid droplets, and destroyed mitochondrial cristae. Defective mtDNA replication with mtDNA depletion seems central to the subcellular pathophysiol. of altered energy metab. and multiorgan failure in FIAU toxicity.
- 13Lebrecht, D., Vargas-Infante, Y. A., Setzer, B., Kirschner, J., and Walker, U. A. (2007) Uridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in mice. Hepatology 45, 72– 79, DOI: 10.1002/hep.21490Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28jlsFGguw%253D%253D&md5=380ea7d7d80484d493c622d08c40980aUridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in miceLebrecht Dirk; Vargas-Infante Yetlanezi A; Setzer Bernhard; Kirschner Janbernd; Walker Ulrich AHepatology (Baltimore, Md.) (2007), 45 (1), 72-9 ISSN:0270-9139.UNLABELLED: Zalcitabine is an antiretroviral nucleoside analogue that exhibits long-term toxicity to hepatocytes by interfering with the replication of mitochondrial DNA (mtDNA). Uridine antagonizes this effect in vitro. In the present study we investigate the mechanisms of zalcitabine-induced hepatotoxicity in mice and explore therapeutic outcomes with oral uridine supplementation. BalbC mice (7 weeks of age, 9 mice in each group) were fed 0.36 mg/kg/d of zalcitabine (corresponding to human dosing adapted for body surface), or 13 mg/kg/d of zalcitabine. Both zalcitabine groups were treated with or without Mitocnol (0.34 g/kg/d), a dietary supplement with high bioavailability of uridine. Liver histology and mitochondrial functions were assessed after 15 weeks. One mouse exposed to high dose zalcitabine died at 19 weeks of age. Zalcitabine induced a dose dependent microvesicular steatohepatitis with abundant mitochondria. The organelles were enlarged and contained disrupted cristae. Terminal transferase dUTP nick end labeling (TUNEL) assays showed frequent hepatocyte apoptosis. mtDNA was depleted in liver tissue, cytochrome c-oxidase but not succinate dehydrogenase activities were decreased, superoxide and malondialdehyde were elevated. The expression of COX I, an mtDNA-encoded respiratory chain subunit was reduced, whereas COX IV, a nucleus-encoded subunit was preserved. Uridine supplementation normalized or attenuated all toxic abnormalities in both zalcitabine groups, but had no effects when given without zalcitabine. Uridine supplementation was without apparent side effects. CONCLUSION: Zalcitabine induces mtDNA-depletion in murine liver with consequent respiratory chain dysfunction, up-regulated synthesis of reactive oxygen species and microvesicular steatohepatitis. Uridine supplementation attenuates this mitochondrial hepatotoxicity without apparent intrinsic effects.
- 14Bailey, C. M., Kasiviswanathan, R., Copeland, W. C., and Anderson, K. S. (2009) R964C mutation of DNA polymerase gamma imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activity. Antimicrob. Agents Chemother. 53, 2610– 2612, DOI: 10.1128/AAC.01659-08Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntFGks7g%253D&md5=2512d3efd67530b0d481d773b1571a7dR964C mutation of DNA polymerase γ imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activityBailey, Christopher M.; Kasiviswanathan, Rajesh; Copeland, William C.; Anderson, Karen S.Antimicrobial Agents and Chemotherapy (2009), 53 (6), 2610-2612CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The R964C mutation of human DNA polymerase γ was recently linked to stavudine (d4T)-mediated mitochondrial toxicity. We utilized pre-steady-state kinetics to det. the effect of this mutation on incorporation of natural substrate dTTP and the active metabolite of d4T (d4TTP). The R964C polymerase γ holoenzyme demonstrated a 33% decrease in dTTP incorporation efficiency and a threefold-lower d4TTP discrimination relative to that of the wild-type polymerase γ, providing a mechanistic basis for genetic predisposition to nucleoside reverse transcriptase inhibitor toxicity.
- 15Fromenty, B., Fisch, C., Berson, A., Lettéron, P., Larrey, D., and Pessayre, D. (1990) Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex II. J. Pharmacol. Exp. Ther. 255, 1377– 1384Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXpsVyksA%253D%253D&md5=deb74f7f13fd3c61efb10feea19c3103Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex IIFromenty, Bernard; Fisch, Cecile; Berson, Alain; Letteron, Philippe; Larrey, Dominique; Pessayre, DominiqueJournal of Pharmacology and Experimental Therapeutics (1990), 255 (3), 1377-84CODEN: JPETAB; ISSN:0022-3565.The effects of amiodarone on the respiration of isolated mouse liver mitochondria were detd. Amiodarone (200 μM) had a biphasic effect on state 4 respiration supported by either glutamate plus malate or succinate. Initially, the respiratory rate was increased. This stimulatory effect was not prevented by oligomycin (an inhibitor of ATP synthase). It was assocd. with marked accumulation of amiodarone in the mitochondria, and with collapse of the mitochondrial membrane potential. This initial uncoupling effect was followed by a progressive decrease in the state 4 respiration rate, leading eventually to marked inhibition. Preincubation for 5 min with amiodarone (200 μM) also decreased markedly ADP-stimulated (state 3) respiration, ATP prodn. and dinitrophenol-stimulated (uncoupled) respiration supported by glutamate plus malate (which donate electrons to complex I), and respiration supported by succinate (which donate electrons to complex II), but did not affect respiration supported by duroquinol (donating electrons to complex III) or by ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine (donating electrons to cytochrome c). Preincubation with amiodarone (150-200 μM) decreased markedly respiration mediated by fatty acids of various chain length and respiration mediated by citrate, a tricarboxylic acid cycle substrate. Thus, amiodarone has a dual effect on mitochondrial respiration. The initial uncoupling effect is probably due to the entry of protonated amiodarone, releasing a proton in the matrix. Accumulation of amiodarone soon leads to inhibition of the respiratory chain at the levels of complex I and complex II and to decreased ATP formation.
- 16Felser, A., Blum, K., Lindinger, P. W., Bouitbir, J., and Krähenbühl, S. (2013) Mechanisms of hepatocellular toxicity associated with dronedarone-a comparison to amiodarone. Toxicol. Sci. 131, 480– 490, DOI: 10.1093/toxsci/kfs298Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFent7w%253D&md5=e7151b62d993396ac9832b40160c262cMechanisms of Hepatocellular Toxicity Associated with Dronedarone-A Comparison to AmiodaroneFelser, Andrea; Blum, Kim; Lindinger, Peter W.; Bouitbir, Jamal; Krahenbuhl, StephanToxicological Sciences (2013), 131 (2), 480-490CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50μM, resp. The cellular ATP content started to decrease at 20μM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concns. of ~10μM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was obsd. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial β-oxidn. at 10μM and amiodarone at 20μM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of β-oxidn. both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo.
- 17Deschamps, D., DeBeco, V., Fisch, C., Fromenty, B., Guillouzo, A., and Pessayre, D. (1994) Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions. Hepatology 19, 948– 961, DOI: 10.1002/hep.1840190422Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXkvF2gtbo%253D&md5=311e193271275d0bf108cea809e94abeInhibition by perhexiline of oxidative phosphorylation and the β-oxidation of fatty acids: Possible role in pseudoalcoholic liver lesionsDeschamps, Dominique; DeBeco, Virginie; Fisch, Cecile; Fromenty, Bernard; Guillouzo, Andre; Pessayre, DominiqueHepatology (Philadelphia, PA, United States) (1994), 19 (4), 948-61CODEN: HPTLD9; ISSN:0270-9139.In an attempt to better understand the mechanisms for pseudoalcoholic liver lesions in human beings, the authors detd. the effects of perhexiline on mitochondrial functions in mice and rats. A first series of studies suggested that protonated perhexiline entered mouse mitochondria along the mitochondrial membrane potential. Release of a proton in the mitochondrial matrix led to uncoupling of oxidative phosphorylation, and accumulation of perhexiline inhibited complexes I and II of the respiratory chain, decreased ATP formation in vitro and decreased the mitochondrial β-oxidn. of long-, medium- and short-chain fatty acids in vitro and in vivo in mice. In cultured rat hepatocytes, exposure for 24 h to 25 μmol/L perhexiline markedly decreased hepatocellular ATP and cell viability. Exposure to 5 μmol/L perhexiline did not modify ATP and viability but decreased the β-oxidn. of palmitic acid uniformly labeled with carbon 14 by 38%, increased hepatocyte triglyceride levels by 98% and produced microvesicular steatosis after 72 h of culture. The authors conclude that perhexiline is concd. inside mitochondria, where it inhibits both oxidative phosphorylation and the mitochondrial β-oxidn. of fatty acids. These effects may contribute to the development of necrosis, steatosis and possibly certain other pseudoalcoholic liver lesions in human beings.
- 18Berson, A., Fau, D., Fornacciari, R., Degove-Goddard, P., Sutton, A., Descatoire, V., Haouzi, D., Lettéron, P., Moreau, A., Feldmann, G., and Pessayre, D. (2001) Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation. J. Hepatol. 34, 261– 269, DOI: 10.1016/S0168-8278(00)00050-7Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXislCksLY%253D&md5=ea9538e36c230f4a7e41e614848f289dMechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activationBerson, Alain; Fau, Daniel; Fornacciari, Roxane; Degove-Goddard, Pamela; Sutton, Angela; Descatoire, Veronique; Haouzi, Delphine; Letteron, Philippe; Moreau, Alain; Feldmann, Gerard; Pessayre, DominiqueJournal of Hepatology (2001), 34 (2), 261-269CODEN: JOHEEC; ISSN:0168-8278. (Elsevier Science Ltd.)Background/Aims: Although sublingual buprenorphine is safely used as a substitution drug in heroin addicts, large over doses or i.v. misuse may cause hepatitis. Buprenorphine is N-dealkylated to norbuprenorphine by CYP3A. Methods: We investigated the mitochondrial effects and metabolic activation of buprenorphine in isolated rat liver mitochondria and microsomes, and its toxicity in isolated rat hepatocytes and treated mice. Results: Whereas norbuprenorphine had few mitochondrial effects, buprenorphine (25-200 μM) concd. in mitochondria, collapsed the membrane potential, inhibited β-oxidn., and both uncoupled and inhibited respiration in rat liver mitochondria. Both buprenorphine and norbuprenorphine (200 μM) underwent CYP3A-mediated covalent binding to rat liver microsomal proteins and both caused moderate glutathione depletion and increased cell calcium in isolated rat hepatocytes, but only buprenorphine also depleted cell ATP and caused necrotic cell death. Four hours after buprenorphine administration to mice (100 nmol/g body wt.), hepatic glutathione was unchanged, while ATP was decreased and serum transaminase increased. This transaminase increase was attenuated by a CYP3A inducer and aggravated by a CYP3A inhibitor. Conclusions: Both buprenorphine and norbuprenorphine undergo metabolic activation, but only buprenorphine impairs mitochondrial respiration and ATP formation. The hepatotoxicity of high concns. or doses of buprenorphine is mainly related to its mitochondrial effects.
- 19Wood, D. M., Alsahaf, H., Streete, P., Dargan, P. I., and Jones, A. L. (2005) Fatality after deliberate ingestion of the pesticide rotenone: a case report. Crit. Care 9, R280– R284, DOI: 10.1186/cc3528Google ScholarThere is no corresponding record for this reference.
- 20Jiang, X. W., Qiao, L., Feng, X. X., Liu, L., Wei, Q. W., Wang, X. W., and Yu, W. H. (2017) Rotenone induces nephrotoxicity in rats: oxidative damage and apoptosis. Toxicol. Mech. Methods 27, 528– 536, DOI: 10.1080/15376516.2017.1333553Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVeqs7bM&md5=ef069e6896d2907dd5b72ba572597c18Rotenone induces nephrotoxicity in rats: oxidative damage and apoptosisJiang, Xiao-Wen; Qiao, Lu; Feng, Xin-xin; Liu, Lin; Wei, Qing-Wei; Wang, Xue-Wei; Yu, Wen-HuiToxicology Mechanisms and Methods (2017), 27 (7), 528-536CODEN: TMMOCP; ISSN:1537-6516. (Taylor & Francis Ltd.)Previous studies have examd. rotenone toxicity on the human central nervous system, esp. in the pathogenesis of Parkinson's disease, but few have investigated the effects of rotenone on the kidney. Here, rotenone-induced nephrotoxicity was evaluated by detg. morphol., biochem., oxidative stress-related, and apoptotic factor alterations in rat renal tissue. Morphol. and biochem. analyzes showed that rotenone administration to rats damaged renal tissue. Western blot results revealed that rotenone-induced oxidative damage, causing overprodn. of glutathione, malonaldehyde, and reactive oxygen species (ROS), and inhibiting superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. Rotenone also decreased the mitochondrial membrane potential and increased voltage-dependent anion channel (VDAC), caspase-3, and caspase-9 protein levels, indicating an assocn. of apoptosis with renal damage. Our results suggest that glutathione, malonaldehyde, and ROS may be signals of rotenone-induced oxidative damage, and that the mitochondrial pathway plays a key role in apoptosis of renal cells following rotenone administration.
- 21Watkins, R. C., Hambrick, E. L., Benjamin, G., and Chavda, S. N. (1990) Isoniazid toxicity presenting as seizures and metabolic acidosis. J. Natl. Med. Assoc. 82, 57– 64Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3c7ls1Cgug%253D%253D&md5=0460cf5e3eb69deb36f24b1df514e839Isoniazid toxicity presenting as seizures and metabolic acidosisWatkins R C; Hambrick E L; Benjamin G; Chavda S NJournal of the National Medical Association (1990), 82 (1), 57, 62, 64 ISSN:0027-9684.The presenting signs and symptoms of isoniazid toxicity are discussed, with a review of the complications and management of this metabolic encephalopathy with B6 pyridoxine. This study supports previous studies in finding that ingestion of more than 80 mg/kg body weight produces severe central nervous system symptoms that are rapidly reversed with intravenous administration of pyridoxine.
- 22Gokhale, Y. A., Vaidya, M. S., Mehta, A. D., and Rathod, N. N. (2009) Isoniazid toxicity presenting as status epilepticus and severe metabolic acidosis. J. Assoc. Physicians India 57, 70– 71Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnisFKgsA%253D%253D&md5=4f87235c860ebb38e2e93ef70b382e71Isoniazid toxicity presenting as status epilepticus and severe metabolic acidosisGokhale Yojana A; Vaidya Meghna S; Mehta A D; Rathod N NThe Journal of the Association of Physicians of India (2009), 57 (), 70-1 ISSN:0004-5772.Isoniazid (INH) is an integral component of treatment of tuberculosis. An acute overdose is potentially fatal and is characterized by the clinical triad of repetitive seizures unresponsive to the usual anticonvulsants, metabolic acidosis with a high anion gap and coma. The diagnosis of INH overdose should be considered in any patient who presents to emergency medical services (EMS) with the triad. We report a patient presenting with multiple generalised tonic clonic (GTC) convulsions with severe metabolic acidosis as a manifestation of INH toxicity.
- 23Isenberg, J. S. and Klaunig, J. E. (2000) Role of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cells. Toxicol. Sci. 53, 340– 351, DOI: 10.1093/toxsci/53.2.340Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhtF2ksL4%253D&md5=3ee6fbf89560bc157a0f28202c7d148aRole of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cellsIsenberg, Jason S.; Klaunig, James E.Toxicological Sciences (2000), 53 (2), 340-351CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Rotenone inhibits spontaneously and chem. induced hepatic tumorigenesis in rodents through the induction of apoptosis. However, the mechanism for the induction of apoptosis by rotenone has not been defined. Mitochondrial dysfunction, in particular the induction of the mitochondrial membrane permeability transition (MPT), has been implicated in the cascade of events involved in the induction of apoptosis. Inhibition of the mitochondrial electron-transport chain reduces the mitochondrial transmembrane potential (Δψm), which may induce the formation of the mitochondrial permeability transition pore and the subsequent MPT. Fluorescent microscopy of Hoechst 33258-stained WB-F344 cells, a rat-liver cell line, was utilized to examine the effect of the mitochondrial respiratory chain inhibitor, rotenone (0.5-5 μM), atractyloside (5-10 μM), and cyclosporin A (2.5-10 μM) on apoptosis. A time- and concn.-dependent increase in liver cell apoptosis was obsd. following treatment with rotenone and atractyloside (11.7- and 7.7-fold, resp., over solvent control). Cotreatment with 7.5- and 10 μM-cyclosporin A for 12 h inhibited the apoptogenicity of 5-μM rotenone treatment. A similar effect was obsd. following cyclosporin A cotreatment with atractyloside. Rotenone induced a rapid increase in apoptosis (within 20 min of treatment). By 2 h of treatment, the morphol. appearance of apoptosis was similar to that obsd. in cultures treated continuously with rotenone for 12 h. Inhibition studies demonstrated that cyclosporin A prevented apoptosis if the exposure to it occurred prior to the 20-min threshold necessary to induce apoptosis by rotenone. Mitochondrial function was examd. by staining with the mitochondrial membrane potential (Δψm)-sensitive fluorochrome, MitoTracker Red (CMXRos) and confirmed utilizing cytofluorometric anal. of DiOC6-stained cells. Rotenone (5.0-μM) and atractyloside (5.0-μM) reduced the percent of CMXRos or DiOC6-pos. (Δψm-pos.) liver cells within 15 min and throughout the duration of the study (6 h) to approx. 65-80% and 50-80% of control. However, co-treatment with concns. of cyclosporin A that inhibited the apoptogenicity of rotenone and atractyloside prevented the rotenone- and atractyloside-induced redn. of the Δψm. Therefore, the apoptogenic effect of rotenone and atractyloside appears to occur rapidly (within 20 min) and is irreversible once mitochondrial damage occurs. The inhibition of the rotenone- and atractyloside-induced apoptosis and mitochondrial dysfunction by cyclosporin A suggests the MPT may be involved in the induction of apoptosis by rotenone.
- 24Mann, A., Pelz, T., Rennert, K., Mosig, A., Decker, M., and Lupp, A. (2017) Evaluation of HepaRG cells for the assessment of indirect drug-induced hepatotoxicity using INH as a model substance. Hum. Cell 30, 267– 278, DOI: 10.1007/s13577-017-0175-9Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotVOlur8%253D&md5=a8360bdfb4378e3bb4c68ea10d18a59eEvaluation of HepaRG cells for the assessment of indirect drug-induced hepatotoxicity using INH as a model substanceMann, Anika; Pelz, Thomas; Rennert, Knut; Mosig, Alexander; Decker, Michael; Lupp, AmelieHuman Cell (2017), 30 (4), 267-278CODEN: HUCEE7; ISSN:1749-0774. (Springer)HepaRG cells are widely used as an in vitro model to assess drug-induced hepatotoxicity. However, only few studies exist so far regarding their suitability to detect the effects of drugs requiring a preceding activation via the cytochrome P 450 (CYP) system. A prototypic substance is the anti-tuberculosis agent INH, which is metabolized into N-acetylhydrazine, which then triggers hepatotoxicity. Therefore, the aim of the present study was to test if this effect can also be detected in HepaRG cells and if it can be counteracted by the known hepatoprotectant silibinin. For this purpose, differentiated HepaRG cells were treated with increasing concns. of INH (0.1-100 mM) or 10 mM INH plus escalating concns. of silibinin (1-100 μM). After 48 h of treatment, cell morphol. and parameters indicating cell vitality, oxidative stress, and liver cell function were assessed. High concns. of INH led to severe histopathol. changes, reduced cell vitality and glutathione content, increased LDH and ASAT release into the medium, enhanced lipid peroxidn., and elevated cleaved caspase-3 expression. Addnl., glycogen depletion and reduced biotransformation capacity were seen at high INH concns., whereas at low concns. an induction of biotransformation enzymes was noticed. Silibinin caused clear-cut protective effects, but with few parameters INH toxicity was even aggravated, most probably due to increased metabolization of INH into its toxic metabolite. In conclusion, HepaRG cells are excellently suited to evaluate the effects of substances requiring prior toxification via the CYP system, such as INH. They addnl. enable the identification of complex substance interactions.
- 25Catta-Preta, M., Mendonca, L. S., Fraulob-Aquino, J., Aguila, M. B., and Mandarim-de-Lacerda, C. A. (2011) A critical analysis of three quantitative methods of assessment of hepatic steatosis in liver biopsies. Virchows Arch. 459, 477– 485, DOI: 10.1007/s00428-011-1147-1Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3Mblt1CjtQ%253D%253D&md5=1a3a1da42048b5d842c5238efe63fc88A critical analysis of three quantitative methods of assessment of hepatic steatosis in liver biopsiesCatta-Preta Mariana; Mendonca Leonardo Souza; Fraulob-Aquino Julio; Aguila Marcia Barbosa; Mandarim-de-Lacerda Carlos AlbertoVirchows Archiv : an international journal of pathology (2011), 459 (5), 477-85 ISSN:.The issue of adequately quantitatively evaluating hepatic steatosis is still unresolved. Therefore, we compared three methods of quantitative assessment. Two groups of mice (n = 10 each) were fed standard chow (10% fat, SC group) or a high-fat diet (60% fat, HF group) for 16 weeks, and hepatic triglyceride (HT) and liver tissue were then studied. Paraplast-embedded tissues stained by hematoxylin and eosin (H-E) were compared to frozen sections stained by Oil Red-O (ORO). In addition, the volume density of steatosis (Vv[steatosis, liver]) was measured by point counting (P-C, sections H-E or ORO) or by image analysis (I-A, sections ORO). HT was significantly higher in the HF group (104% greater, P = 0.0004) than in the SC group. With P-C and H-E, Vv[steatosis, liver] was 4.80 ± 0.90% in the SC group and 33.50 ± 3.17% in the HF group (600% greater, P < 0.0001). With P-C and ORO, Vv[steatosis, liver] was 4.86 ± 0.89% in the SC group and 25.21 ± 1.27% in the HF group (420% greater, P < 0.0001). With I-A and ORO, Vv[steatosis, liver] was 4.17 ± 0.85% in the SC group and 23.35 ± 1.58% in the HF group (460% greater, P < 0.0001). Correlations between Vv[steatosis, liver] and HT were strong and significant in all methods. In conclusion, all methods were appropriate and reproducible. In P-C and H-E, there is a slight overestimation of steatosis in the HF animals in comparison to frozen sections and ORO; in frozen sections, differences between P-C and I-A are insignificant.
- 26Massart, J., Begriche, K., Buron, N., Porceddu, M., Borgne-Sanchez, A., and Fromenty, B. (2013) Drug-induced inhibition of mitochondrial fatty acid oxidation and steatosis. Curr. Pathobiol. Rep. 1, 147– 157, DOI: 10.1007/s40139-013-0022-yGoogle ScholarThere is no corresponding record for this reference.
- 27Tandra, S., Yeh, M. M., Brunt, E. M., Vuppalanchi, R., Cummings, O. W., Ünalp-Arida, A., Wilson, L. A., and Chalasani, N. (2011) Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease. J. Hepatol. 55, 654– 659, DOI: 10.1016/j.jhep.2010.11.021Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MfmslShtw%253D%253D&md5=fd55ac974d2b6a4b3d5495e480f530a9Presence and significance of microvesicular steatosis in nonalcoholic fatty liver diseaseTandra Sweta; Vuppalanchi Raj; Cummings Oscar W; Yeh Matthew M; Brunt Elizabeth M; Unalp-Arida Aynur; Wilson Laura A; Chalasani NagaJournal of hepatology (2011), 55 (3), 654-659 ISSN:.BACKGROUND & AIMS: Liver biopsies from patients with nonalcoholic fatty liver disease (NAFLD) sometimes exhibit non-zonal aggregates of hepatocytes with microvesicular steatosis, but its prevalence and significance are unclear. In this study, we have evaluated the frequency of microvesicular steatosis and assessed its association with histological markers of disease severity in a large sample of NAFLD liver biopsies. METHODS: Liver biopsies from a large cohort of adults who participated in two studies conducted by the NASH Clinical Research Network (NASH CRN) were included in this cross-sectional study. Liver histology was assessed centrally and various histological features scored in a systematic fashion. The relationship between microvesicular steatosis and various histological features that characterize NAFLD was tested by multiple logistic regression, after controlling for age, gender, race, body mass index, and diabetes. RESULTS: Among 1022 liver biopsies included, 102 (10%) had microvesicular steatosis. No demographic differences were noted between patients with or without microvesicular steatosis. The presence of microvesicular steatosis was associated with higher grades of steatosis (p<0.001), ballooning cell injury (p<0.001), presence of Mallory-Denk bodies (p<0.007), presence of megamitochondria (p<0.0001), higher NAS scores (p<0.0001), more advanced fibrosis (p<0.0001), and diagnosis of borderline or definite NASH (p<0.0001). CONCLUSIONS: Microvesicular steatosis correlates with more advanced histology of NAFLD. Longitudinal studies are needed to address the role of microvesicular steatosis in mediating cellular injury and disease progression in NAFLD.
- 28Amacher, D. E. (2012) The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin. Drug Metab. Toxicol. 8, 335– 347, DOI: 10.1517/17425255.2012.658041Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisFWitLw%253D&md5=ff76f002fd099276dad9bd5e742a8902The primary role of hepatic metabolism in idiosyncratic drug-induced liver injuryAmacher, David E.Expert Opinion on Drug Metabolism & Toxicology (2012), 8 (3), 335-347CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. Introduction: Idiosyncratic drug-induced liver injury (DILI) is a rare, serious and sometimes fatal condition that lacks an effective clin. countermeasure. Polymorphisms of bioactivation/toxification pathways via the Phase I drug-metabolizing enzymes, Phase II detoxification reactions and Phase III excretion/transport, together with immunol. factors, are predisposing factors for some DILI.Areas covered: This review focuses on the seminal role of hepatic drug metab. in the idiosyncratic toxicity response and the potential role of genetic polymorphisms in specific drug-metabolizing enzymes or transporters. Furthermore, the article looks at recent developments for the assessment of those mechanisms, in order to avoid them in novel drug candidates that are still under development. Examples of proposed or confirmed metabolic mechanisms from the current literature for marketed or previously marketed drugs are summarized in detail. The contributions of Phase I, II and III and other enzymic pathways in the idiosyncratic response are reviewed with particular emphasis on gene polymorphisms that might explain why some individuals respond in an aberrant manner.Expert opinion: Toxicologists continue to focus their efforts to define the idiosyncratic response at the biochem. and mol. levels. This has resulted in the development of some early drug screening tools based on such characteristics as the daily dose, metabolite covalent binding and polymorphisms in drug-metabolizing enzymes. While it will take years to fully assess the impact of these recently developed assessment tools, research on genetically based differences in hepatic metabolic pathways will continue, aided by the establishment of DILI registries for improved patient access.
- 29McGill, M. R. and Jaeschke, H. (2019) Animal models of drug-induced liver injury. Biochim. Biophys. Acta, Mol. Basis Dis. 1865, 1031– 1039, DOI: 10.1016/j.bbadis.2018.08.037Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1OrsLrF&md5=8f73f53aa566cd81f23521a324fa1ae1Animal models of drug-induced liver injuryMcGill, Mitchell R.; Jaeschke, HartmutBiochimica et Biophysica Acta, Molecular Basis of Disease (2019), 1865 (5), 1031-1039CODEN: BBADEX; ISSN:0925-4439. (Elsevier B.V.)A review. Drug-induced liver injury (DILI) presents unique challenges for consumers, clinicians, and regulators. It is the most common cause of acute liver failure in the US. It is also one of the most common reasons for termination of new drugs during pre-clin. testing and withdrawal of new drugs post-marketing. DILI is generally divided into two forms: intrinsic and idiosyncratic. Many of the challenges with DILI are due in large part to poor understanding of the mechanisms of toxicity. Although useful models of intrinsic DILI are available, they are frequently misused. Modeling idiosyncratic DILI presents greater challenges, but promising new models have recently been developed. The purpose of this manuscript is to provide a crit. review of the most popular animal models of DILI, and to discuss the future of DILI research.
- 30Church, R. J., Wu, H., Mosedale, M., Sumner, S. J., Pathmasiri, W., Kurtz, C. L., Pletcher, M. T., Eaddy, J. S., Pandher, K., Singer, M., Batheja, A., Watkins, P. B., Adkins, K., and Harrill, A. H. (2014) A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis. Toxicol. Sci. 140, 481– 492, DOI: 10.1093/toxsci/kfu094Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1ygtrrL&md5=2c2c6fce621e868d096b5c373fb5ae78A Systems Biology Approach Utilizing a Mouse Diversity Panel Identifies Genetic Differences Influencing Isoniazid-Induced Microvesicular SteatosisChurch, Rachel J.; Wu, Hong; Mosedale, Merrie; Sumner, Susan J.; Pathmasiri, Wimal; Kurtz, Catherine L.; Pletcher, Mathew T.; Eaddy, John S.; Pandher, Karamjeet; Singer, Monica; Batheja, Ameesha; Watkins, Paul B.; Adkins, Karissa; Harrill, Alison H.Toxicological Sciences (2014), 140 (2), 481-492CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)Isoniazid (INH), the mainstay therapeutic for tuberculosis infection, has been assocd. with rare but serious hepatotoxicity in the clinic. However, the mechanisms underlying inter-individual variability in the response to this drug have remained elusive. A genetically diverse mouse population model in combination with a systems biol. approach was utilized to identify transcriptional changes, INH-responsive metabolites, and gene variants that contribute to the liver response in genetically sensitive individuals. Sensitive mouse strains developed severe microvesicular steatosis compared with corresponding vehicle control mice following 3 days of oral treatment with INH. Genes involved in mitochondrial dysfunction were enriched among liver transcripts altered with INH treatment. Those assocd. with INH treatment and susceptibility to INH-induced steatosis in the liver included apolipoprotein A-IV, lysosomal-assocd. membrane protein 1, and choline phosphotransferase 1. These alterations were accompanied by metabolomic changes including reduced levels of glutathione and the choline metabolites betaine and phosphocholine, suggesting that oxidative stress and reduced lipid export may addnl. contribute to INH-induced steatosis. Finally, genome-wide assocn. mapping revealed that polymorphisms in perilipin 2 were linked to increased triglyceride levels following INH treatment, implicating a role for inter-individual differences in lipid packaging in the susceptibility to INH-induced steatosis. Taken together, our data suggest that INH-induced steatosis is caused by not one, but multiple events involving lipid retention in the livers of genetically sensitive individuals. This work also highlights the value of using a mouse diversity panel to investigate drug-induced responses across a diverse population.
- 31Stewart, J. D., Horvath, R., Baruffini, E., Ferrero, I., Bulst, S., Watkins, P. B., Fontana, R. J., Day, C. P., and Chinnery, P. F. (2010) Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology 52, 1791– 1796, DOI: 10.1002/hep.23891Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFOnsrvE&md5=45eac0bcd5428d1be9cae5b888c69febPolymerase γ gene POLG Determines the Risk of Sodium Valproate-Induced Liver ToxicityStewart, Joanna D.; Horvarth, Rita; Baruffin, Enrico; Ferrero, Iliana; Bulst, Stefanie; Watkins, Paul B.; Fontana, Robert J.; Day, Christopher P.; Chinnery, PatrickHepatology (Hoboken, NJ, United States) (2010), 52 (5), 1791-1796CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)Sodium valproate (VPA) is widely used throughout the world to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy. VPA toxicity is an uncommon but potentially fatal cause of idiosyncratic liver injury. Rare mutations in POLG, which codes for the mitochondrial DNA polymerase γ (poly), cause Aplers-Huttenlocher syndrome (AHS). AHS is a neurometabolic disorder assocd. with an increased risk of developing fatal VPA hepatoxicity. We therefore set out to det. whether common genetic variants in POLG explain why some otherwise healthy individuals develop VPA hepatotoxicity. We carried out a prospective study of subjects enrolled in the Drug Induced Liver Injury Network (DILIN) from 2004 to 2008 through five US centers. POLG was sequenced and the functional consequences of VPA and novel POLG variants were evaluated in primary human cell lines and the yeast model system Saccharomyces cerevisiae. Heterozygous genetic variation in POLG was strongly assocd. with VPA- induced liver toxicity (odds ratio = 23.6, 95% confidence interval [CI] = 8.4-65.8, p = 5.1 × 10-7). This was principally due to the p.Q1236H substitution which compromised poly function in yeast. Therapeutic does of VPA inhibited human cellular proliferation and high doses caused nanopoptotic cell death, which was not mediated through mitochondrial DNA Depletion, mutation, or a defect of fatty acid metab. Conclusion: These findings implicate impaired liver regeneration in VPA toxicity and show that prospective genetic testing of POLG will identify individuals at high risk of this potentially fatal consequence of treatment.
- 32Lucena, M. I., García-Martín, E., Andrade, R. J., Martínez, C., Stephens, C., Ruiz, J. D., Ulzurrun, E., Fernandez, M. C., Romero-Gomez, M., Castiella, A., Planas, R., Durán, J. A., De Dios, A. M., Guarner, C., Soriano, G., Borraz, Y., and Agundez, J. A. (2010) Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology 52, 303– 312, DOI: 10.1002/hep.23668Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpsFShtbc%253D&md5=72eb0f4a53f44f51e1604e8a991fb47bMitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injuryLucena, M. Isabel; Garcia-Martin, Elena; Andrade, Raul J.; Martinez, Carmen; Stephens, Camilla; Ruiz, Jhon D.; Ulzurrun, Eugenia; Fernandez, M. Carmen; Romero-Gomez, Manuel; Castiella, Augustin; Planas, Ramon; Duran, Jose Antonio; De Dios, Ana Melcon; Guarner, Carlos; Soriano, German; Borraz, Yolanda; Agundez, Jose A. G.Hepatology (Hoboken, NJ, United States) (2010), 52 (1), 303-312CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible assocns. between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2 Val16Ala) and glutathione peroxidase (GPX1 Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex- and age-matched controls were analyzed. The SOD2 and GPX1 genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quant. polymerase chain reaction, resp. The statistical power to detect the effect of variant alleles with the obsd. odds ratio (OR) was 98.2% and 99.7% for bilateral assocn. of SOD2 and GPX1, resp. The SOD2 Ala/Ala genotype was assocd. with cholestatic/mixed damage (OR = 2.3; 95% confidence interval [CI] = 1.4-3.8; cor. P [Pc] = 0.0058), whereas the GPX1 Leu/Leu genotype was assocd. with cholestatic injury (OR = 5.1; 95%CI = 1.6-16.0; Pc = 0.0112). The presence of two or more combined risk alleles (SOD2 Ala and GPX1 Leu) was more frequent in DILI patients (OR = 2.1; 95%CI = 1.4-3.0; Pc = 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the SOD2 Ala/Ala genotype (OR = 3.6; 95%CI = 1.4-9.3; Pc = 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR = 3.0; 95%CI = 1.7-5.5; Pc = 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR = 16.0; 95%CI = 1.8-146.1; Pc = 0.009). Patients homozygous for the SOD2 Ala allele and the GPX1 Leu allele are at higher risk of developing cholestatic DILI. SOD2 Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates.
- 33Borgne-Sanchez, A., and Fromenty, B. (2018) Mitochondrial dysfunction in drug-induced liver injury. In Drug-Induced Mitochondrial Dysfunction: Progress Towards the Clinics (Will, Y., and Dykens, J. A., Eds.) 2nd ed., pp 49– 72, John Wiley & Sons, Hoboken.Google ScholarThere is no corresponding record for this reference.
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- 1Labbe, G., Pessayre, D., and Fromenty, B. (2008) Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335– 353, DOI: 10.1111/j.1472-8206.2008.00608.x1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptlaltr0%253D&md5=a60eddefd1f7444b9494e4981333f3b8Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studiesLabbe, Gilles; Pessayre, Dominique; Fromenty, BernardFundamental & Clinical Pharmacology (2008), 22 (4), 335-353CODEN: FCPHEZ; ISSN:0767-3981. (Wiley-Blackwell)A review. Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects such as lactic acidosis and rhabdomyolysis in some patients. By severely altering mitochondrial function in the liver, drugs can induce microvesicular steatosis, a potentially severe lesion that can be assocd. with profound hypoglycemia and encephalopathy. They can also trigger hepatic necrosis and/or apoptosis, causing cytolytic hepatitis, which can evolve into liver failure. Milder mitochondrial dysfunction, sometimes combined with an inhibition of triglyceride egress from the liver, can induce macrovacuolar steatosis, a benign lesion in the short term. However, in the long term this lesion can evolve in some individuals towards steatohepatitis, which itself can progress to extensive fibrosis and cirrhosis. As liver injury caused by mitochondrial dysfunction can induce the premature end of clin. trials, or drug withdrawal after marketing, it should be detected during the preclin. safety studies. Several in vitro and in vivo investigations can be performed to det. if newly developed drugs disturb mitochondrial fatty acid oxidn. (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition (MPT) pore. As drugs can be deleterious for hepatic mitochondria in some individuals but not in others, it may also be important to use novel animal models with underlying mitochondrial and/or metabolic abnormalities. This could help us to better predict idiosyncratic liver injury caused by drug-induced mitochondrial dysfunction.
- 2Cho, T. and Uetrecht, J. (2017) How reactive metabolites induce an immune response that sometimes leads to an idiosyncratic drug reaction. Chem. Res. Toxicol. 30, 295– 314, DOI: 10.1021/acs.chemrestox.6b003572https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslagsb3M&md5=04137ee96f32fea06c39a22eea4e4200How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug ReactionCho, Tiffany; Uetrecht, JackChemical Research in Toxicology (2017), 30 (1), 295-314CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addn., evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-assocd. mol. pattern mols. that activate antigen presenting cells. Both are required for an immune response. In addn., drugs may induce an immune response through inflammasome activation. The authors have found examples in which the ability to activate inflammasomes differentiated drugs that cause IDRs from similar drugs that do not. There are other hypotheses that do not involve an immune mechanism such as mitochondrial injury and bile salt export pump (BSEP) inhibition. With some possible exception, these hypotheses are unlikely to be able to completely explain IDRs. However, some types of mitochondrial injury or BSEP inhibition could produce danger signals. The major mechanism that protects individuals from IDRs appears to be immune tolerance. Consistent with this hypothesis, the authors used checkpoint inhibition to develop the first animal model of idiosyncratic drug-induced liver injury that has the same characteristics as the idiosyncratic injury in humans. This was accomplished by treating Pd-1-/- mice with anti-CTLA-4 antibodies and amodiaquine. The combination of the Pd-1-/- mouse and anti-CTLA-4 also unmasks the ability of other drugs such as isoniazid to cause delayed type liver injury. This model should allow rigorous testing of mechanistic hypotheses that was impossible in the past.
- 3Porceddu, M., Buron, N., Roussel, C., Labbe, G., Fromenty, B., and Borgne-Sanchez, A. (2012) Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria. Toxicol. Sci. 129, 332– 345, DOI: 10.1093/toxsci/KFS1973https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVSmsrnP&md5=55bab720ede256a4dc3cb9d4f5283954Prediction of Liver Injury Induced by Chemicals in Human With a Multiparametric Assay on Isolated Mouse Liver MitochondriaPorceddu, Mathieu; Buron, Nelly; Roussel, Celestin; Labbe, Gilles; Fromenty, Bernard; Borgne-Sanchez, AnnieToxicological Sciences (2012), 129 (2), 332-345CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)Drug-induced liver injury (DILI) in humans is difficult to predict using classical in vitro cytotoxicity screening and regulatory animal studies. This explains why numerous compds. are stopped during clin. trials or withdrawn from the market due to hepatotoxicity. Thus, it is important to improve early prediction of DILI in human. In this study, we hypothesized that this goal could be achieved by investigating drug-induced mitochondrial dysfunction as this toxic effect is a major mechanism of DILI. To this end, we developed a high-throughput screening platform using isolated mouse liver mitochondria. Our broad spectrum multiparametric assay was designed to detect the global mitochondrial membrane permeabilization (swelling), inner membrane permeabilization (transmembrane potential), outer membrane permeabilization (cytochrome c release), and alteration of mitochondrial respiration driven by succinate or malate/glutamate. A pool of 124 chems. (mainly drugs) was selected, including 87 with documented DILI and 37 without reported clin. hepatotoxicity. Our screening assay revealed an excellent sensitivity for clin. outcome of DILI (94 or 92% depending on cutoff) and a high pos. predictive value (89 or 82%). A highly significant relationship between drug-induced mitochondrial toxicity and DILI occurrence in patients was calcd. (p < 0.001). Moreover, this multiparametric assay allowed identifying several compds. for which mitochondrial toxicity had never been described before and even helped to clarify mechanisms with some drugs already known to be mitochondriotoxic. Investigation of drug-induced loss of mitochondrial integrity and function with this multiparametric assay should be considered for integration into basic screening processes at early stage to select drug candidates with lower risk of DILI in human. This assay is also a valuable tool for assessing the mitochondrial toxicity profile and investigating the mechanism of action of new compds. and marketed compds.
- 4Ramachandran, A., Visschers, R. G., Duan, L., Akakpo, J. Y., and Jaeschke, H. (2018) Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives. J. Clin. Transl. Res. 4, 75– 100, DOI: 10.18053/jctres.04.201801.0054https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVCisb7K&md5=1c07c344415a1338ea980d88bf2f50cfMitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectivesRamachandran, Anup; Duan, Luqi; Akakpo, Jephte Y.; Jaeschke, HartmutJournal of Clinical and Translational Research (2018), 4 (1), 75-100CODEN: JCTRGT; ISSN:2424-810X. (Whioce Publishing Pte. Ltd.)Mitochondria are crit. cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metab., as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examd. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clin. useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clin. relevant animal models and more translational studies using mechanistic biomarkers are crit. for progress in this area. Relevance for patients: This review focuses on the role of mitochondrial dysfunction in liver injury mechanisms of clin. important drugs like acetaminophen, diclofenac, rifampicin, isoniazid, amiodarone and others. A better understanding of the mechanisms in animal models and their translation to patients will be crit. for the identification of new therapeutic targets.
- 5Begriche, K., Massart, J., Robin, M. A., Borgne-Sanchez, A., and Fromenty, B. (2011) Drug-induced toxicity on mitochondria and lipid metabolism. Mechanistic diversity and deleterious consequences for the liver. J. Hepatol. 54, 773– 794, DOI: 10.1016/j.jhep.2010.11.0065https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjs12hsr8%253D&md5=ff6a28895ffcc230cb438565b164f207Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liverBegriche, Karima; Massart, Julie; Robin, Marie-Anne; Borgne-Sanchez, Annie; Fromenty, BernardJournal of Hepatology (2011), 54 (4), 773-794CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)A review. Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P 450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clin. and pathol. features. Microvesicular steatosis, a potentially severe liver lesion usually assocd. with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidn. (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate redn. of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-assocd. triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overprodn. of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent mol., genetic predispositions (in particular those involving mitochondrial enzymes), alc. intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).
- 6Cho, T., Wang, X., and Uetrecht, J. (2019) Rotenone increases isoniazid toxicity but does not cause significant liver injury: implications for the hypothesis that inhibition of the mitochondrial electron transport chain is a common mechanism of idiosyncratic drug-induced liver injury. Chem. Res. Toxicol. 32, 1423– 1431, DOI: 10.1021/acs.chemrestox.9b001166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtF2gsb%252FP&md5=b10936e23ac156bc73888f537892ad63Rotenone Increases Isoniazid Toxicity but Does Not Cause Significant Liver Injury: Implications for the Hypothesis that Inhibition of the Mitochondrial Electron Transport Chain Is a Common Mechanism of Idiosyncratic Drug-Induced Liver InjuryCho, Tiffany; Wang, Xijin; Uetrecht, JackChemical Research in Toxicology (2019), 32 (7), 1423-1431CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Idiosyncratic drug reactions (IDRs) significantly increase the risk of failure in drug development. The major IDR leading to drug candidate failure is idiosyncratic drug-induced liver injury (IDILI). Although most evidence suggests that IDRs are mediated by the immune system, there are other hypotheses, such as mitochondrial dysfunction. Many pharmaceutical companies routinely screen for mitochondrial toxicity in an attempt to "derisk" drug candidates. However, the basic hypothesis has never been rigorously tested. A major assay used for this screening involves measurement of inhibition of the mitochondrial electron transport chain. One study found that the combination of rotenone and isoniazid, which inhibit mitochondrial complex I and II, resp., were synergistic in causing hepatocyte toxicity in vitro and suggested the combination of another drug that inhibited complex I would increase the risk of isoniazid-induced liver injury in patients. We tested this hypothesis in vivo where wild-type and PD-1-/- mice administered anti-CTLA-4, our impaired immune tolerance mouse model, were given 0.02% (w/v) rotenone in water or 0.1%, 0.05%, and 0.01% (wt./wt.) rotenone alone or in combination with isoniazid in food. The cotreatment led to lethality in 100% of the animals receiving 0.1% rotenone and 0.2% isoniazid and 83% of the animals cotreated with 0.05% rotenone and 0.2% isoniazid in food. Nevertheless, there was no significant increase in GLDH or histol. evidence of liver injury. No signs of toxicity were obsd. in any of the mice given rotenone or isoniazid alone. Even though inhibition of the mitochondrial electron transport chain did not lead to significant liver toxicity, it could provide danger signals that promote immune-mediated liver injury. However, rotenone did not significantly increase the liver injury induced by isoniazid in our impaired immune tolerance model. Overall, we conclude that inhibition of the mitochondrial electron transport chain is not a significant mechanism of IDILI.
- 7Fromenty, B. and Pessayre, D. (1995) Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101– 154, DOI: 10.1016/0163-7258(95)00012-67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXnvVKrs78%253D&md5=16297ef1c7df483cd4d6504679fa4671Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicityFromenty, Bernard; Pessayre, DominiquePharmacology & Therapeutics (1995), 67 (1), 101-54CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)A review with many refs. Severe and prolonged impairment of mitochondrial β-oxidn. leads to microvesicular steatosis, and, in severe forms, to liver failure, coma death. Impairment of mitochondrial β-oxidn. may be either genetic or acquired, and different causes may add their effects to inhibit β-oxidn. severely and trigger the syndrome. Drugs and some endogenous compds. can sequester CoA and/or inhibit mitochondrial β-oxidn. enzymes (aspirin, valproic acid, tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine and tianeptine); they may inhibit both mitochondrial β-oxidn. and oxidative phosphorylation (endogenous bile acids, amiodarone, perhexiline and diethylaminoethoxyhesestrol), or they may impair mitochondrial DNA transcription (interferon-α), or decrease mitochondrial DNA replication (dideoxynucleoside analogs), while other compds. (ethanol, female sex hormones) act through a combination of different mechanisms. Any investigational mol. should be screened for such effects.
- 8McKenzie, R., Fried, M. W., Sallie, R., Conjeevaram, H., Di Bisceglie, A. M., Park, Y., Savarese, B., Kleiner, D., Tsokos, M., Luciano, C. (1995) Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N. Engl. J. Med. 333, 1099– 1105, DOI: 10.1056/NEJM1995102633317028https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjvVWg&md5=d91c2cfd5401644b5720395eb30b4144Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analog for chronic hepatitis BMcKenzie, Robin; Fried, Michael W.; Sallie, Richard; Conjeevaram, Hari; Di Bisceglie, Adrian M.; Park, Yoon; Savarese, Barbara; Kleiner, David; Tsokos, Maria; et al.New England Journal of Medicine (1995), 333 (17), 1099-105CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)We describe severe and unexpected multisystem toxicity that occurred during a study of the antiviral nucleoside analog fialuridine (1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil, or FIAU) as therapy for chronic hepatitis B virus infection. Fifteen patients with chronic hepatitis B were randomly assigned to receive fialuridine at a dose of either 0.10 or 0.25 mg per kg of body wt. per day for 24 wk and were monitored every 1 to 2 wk by means of a phys. examn., blood tests, and testing for hepatitis B virus markers. During the 13th week lactic acidosis and liver failure suddenly developed in one patient. The study was terminated on an emergency basis, and all treatment with fialuridine was discontinued. Seven patients were found to have severe hepatotoxicity, with progressive lactic acidosis, worsening jaundice, and deteriorating hepatic synthetic function despite the discontinuation of fialuridine. Three other patients had mild hepatotoxicity. Several patients also had pancreatitis, neuropathy, or myopathy. Of the seven patients with severe hepatotoxicity, five died and two survived after liver transplantation. Histol. anal. of liver tissue revealed marked accumulation of microvesicular and macrovesicular fat, with minimal necrosis of hepatocytes or architectural changes. Electron microscopy showed abnormal mitochondria and the accumulation of fat in hepatocytes. In patients with chronic hepatitis B, treatment with fialuridine induced a severe toxic reaction characterized by hepatic failure, lactic acidosis, pancreatitis, neuropathy, and myopathy. This toxic reaction was probably caused by widespread mitochondrial damage and may occur infrequently with other nucleoside analogs.
- 9Mak, L. Y., Seto, W. K., Lai, C. L., and Yuen, M. F. (2016) DNA polymerase inhibitors for treating hepatitis B: a safety evaluation. Expert Opin. Drug Saf. 15, 383– 392, DOI: 10.1517/14740338.2016.11395739https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitlOrur0%253D&md5=0534d0be3cb9ec93f175893248dea76cDNA polymerase inhibitors for treating hepatitis B: a safety evaluationMak, Lung-Yi; Seto, Wai-Kay; Lai, Ching-Lung; Yuen, Man-FungExpert Opinion on Drug Safety (2016), 15 (3), 383-392CODEN: EODSA9; ISSN:1474-0338. (Taylor & Francis Ltd.)Oral nucleoside/ nucleotide analogs (NAs) are currently the mainstay of treatment for patients with chronic hepatitis B virus (HBV) infection. They are generally safe to use. However, since their approval in the last decade and a half, the literature has reported adverse effects assocd. with the use of NA in HBV patients. A comprehensive review on the drug safety is lacking. Significant adverse effects assocd. with NA use in HBV patients including muscle toxicity, peripheral neuropathy, nephrotoxicity and lactic acidosis are discussed. The reported prevalence of each adverse effect, as well as their predictive factors, reversibility and their use in pregnancy and lactating mothers are covered in this review. Novel data regarding reno-protective effect of telbivudine are also discussed. Use of NA in HBV is generally safe. Uncommon adverse effects can be minimized or detected early if clinicians exercise adequate precautions when using NA for at-risk populations with regular monitoring.
- 10Igoudjil, A., Begriche, K., Pessayre, D., and Fromenty, B. (2006) Mitochondrial, metabolic and genotoxic effects of antiretroviral nucleoside reverse-transcriptase inhibitors. Anti-Infect. Agents Med. Chem. 5, 273– 292, DOI: 10.2174/18715210677769787110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmsVOitbY%253D&md5=ce2be55536e46355e1cf92e7459b7313Mitochondrial, metabolic and genotoxic effects of antiretroviral nucleoside reverse-transcriptase inhibitorsIgoudjil, Anissa; Begriche, Karima; Pessayre, Dominique; Fromenty, BernardAnti-Infective Agents in Medicinal Chemistry (2006), 5 (3), 273-292CODEN: AAMCC2; ISSN:1871-5214. (Bentham Science Publishers Ltd.)A review. Nucleoside reverse-transcriptase inhibitors (NRTIs), including stavudine (d4T), zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC) and abacavir (ABC), inhibit/terminate the reverse transcription of the HIV virus, and markedly improve life expectancy and quality of life in HIV-infected patients. This progress, however, has come at the price of frequent side effects. NRTIs can cause myopathy, cardiomyopathy, pancreatitis, peripheral neuropathy, lipodystrophy, hepatic steatosis, lactic acidosis and/or liver failure. Most of these adverse effects have been ascribed to the inhibition/termination of mitochondrial DNA (mtDNA) replication, thus depleting mtDNA. Among NRTIs, the so-called "D-drugs" (ddC, ddI, d4T) seem to be the most potent inhibitors of mitochondrial DNA polymerase γ and mtDNA replication. MtDNA depletion impairs the synthesis of mtDNA-encoded respiratory chain polypeptides. In turn, the depressed respiratory chain activity can secondarily inhibit fatty acid oxidn. (FAO), pyruvate dehydrogenase and the tricarboxylic acid cycle, thus possibly leading to steatosis and lactic acidosis. The partial block in the flow of electrons also increases the generation of reactive oxygen species (ROS) by overly reduced respiratory chain complexes, and can also lead to cell death. Importantly, both the therapeutic effects of nucleoside analogs and their mtDNA-depleting action require their initial transformation into the triphosphate derivs. This activation pathway competes with conjugation and/or degrdn. pathways. Exogenous and endogenous factors can diversely modulate these anabolic and catabolic pathways, to modulate antiretroviral efficacy and toxicity. Importantly, NRTIs can impair mitochondrial function and cell homeostasis without depleting mtDNA. Possible mechanisms could include the accumulation of oxidative lesions and mutations in mtDNA, drug-induced inhibition of the adenine nucleotide translocator, diverse effects on FAO enzymes and/or cofactors such as L-carnitine, and also genotoxic effects on nDNA. Some of these "mtDNA-unrelated" effects could disturb lipid homeostasis and participate to cell death in some tissues. Although it is still unclear why different nucleoside analogs tend to have different tissue-selective toxicities, and why some individuals may be more susceptible, recent data allow us to put forward some hypotheses.
- 11Wang, Y., Lin, Z., Liu, Z., Harris, S., Kelly, R., Zhang, J., Ge, W., Chen, M., Borlak, J., and Tong, W. (2013) A unifying ontology to integrate histological and clinical observations for drug-induced liver injury. Am. J. Pathol. 182, 1180– 1187, DOI: 10.1016/j.ajpath.2012.12.03311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXksFaksL8%253D&md5=ab75c26b3ae1cb7c4a0f26d9654da2b1A Unifying Ontology to Integrate Histological and Clinical Observations for Drug-Induced Liver InjuryWang, Yuping; Lin, Zhi; Liu, Zhichao; Harris, Stephen; Kelly, Reagan; Zhang, Jie; Ge, Weigong; Chen, Minjun; Borlak, Jurgen; Tong, WeidaAmerican Journal of Pathology (2013), 182 (4), 1180-1187CODEN: AJPAA4; ISSN:0002-9440. (Elsevier B.V.)Drug-induced liver injury (DILI) may present any morphol. characteristic of acute or chronic liver disease with no standardized terminol. in place. Defining lexemes of DILI histopathol. would allow the development of advanced knowledge discovery and data mining tools for across comparisons of publicly available information. For these purposes, a DILI ontol. (DILIo) was developed by using the Unified Medical Language System tool and the standardized terminol. of the Systematized Nomenclature of Medicine-Clin. Terms (SNOMED CT). The DILIo was entrained on findings of 114 US Food and Drug Administration-approved drugs by extg. all clin. DILI-related histopathol. descriptions for 1082 liver biopsy samples, which were then analyzed using the Unified Medical Language System MetaMap and subsequently mapped to the SNOMED CT. The DILIo provides a std. means to describe and organize liver injury induced by drugs, enabling comparative anal. of drugs within and across histopathol. terms. The anal. showed that flutamide, troglitazone, diclofenac, isoniazid, and tamoxifen were reported to have the most diverse histopathol. observations in liver biopsy. Necrosis, cholestasis, fatty degeneration, fibrosis, infiltrate, and hepatic necrosis were the most frequent terms used as descriptors of histopathol. features of DILI. In conclusion, DILIo entrains different algorithms for an efficient meta-anal. of published findings for an improved understanding of mechanisms and clin. characteristics of DILI.
- 12Lewis, W., Griniuviene, B., Tankersley, K. O., Levine, E. S., Montione, R., Engelman, L., de Courten-Myers, G., Ascenzi, M. A., Hornbuckle, W. E., Gerin, J. L., and Tennant, B. C. (1997) Depletion of mitochondrial DNA, destruction of mitochondria, and accumulation of lipid droplets result from fialuridine treatment in woodchucks (Marmota monax). Lab. Invest. 76, 77– 8712https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhsVCisr4%253D&md5=9c305de0ca7c11b3aac2dc0a10b6e2ebDepletion of mitochondrial DNA, destruction of mitochondria, and accumulation of lipid droplets result from fialuridine treatment in woodchucks (Marmota monax)Lewis, William; Griniuviene, Brone; Tankersley, Kevin O.; Levine, Eric S.; Montione, Richard; Engelman, Laura; De Courten-Myers, Gabrielle; Ascenzi, Mary A.; Hornbuckle, William E.; et al.Laboratory Investigation (1997), 76 (1), 77-87CODEN: LAINAW; ISSN:0023-6837. (Williams & Wilkins)Fialuridine (FIAU, 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil) is toxic to liver, heart, muscle, and nerve in clin. trials for chronic viral hepatitis (CH). Mitochondrial toxicity was hypothesized. To address pathophysiol. mechanisms, we examd. mitochondrial changes in FIAU-treated woodchucks (WC) with CH from woodchuck hepatitis virus infection. WC (with and without CH from woodchuck hepatitis virus infection) were treated with FIAU (1.5 mg/kg/day) for 12 wk. WC were killed. Liver, heart, skeletal muscle, and kidney samples underwent DNA extn. and were analyzed ultrastructurally (TEM). Myocardium, skeletal muscles, and liver samples were analyzed histol. Abundance of hepatic, myocardial, muscle, and kidney mtDNA decreased in FIAU-treated WC, but the magnitude varied. MtDNA decreased 55% in heart, 65% in kidney, 74% in liver, and 87% in muscle (for each tissue: FIAU-treated vs. FIAU-untreated). Cellular damage was characterized ultrastructurally by mitochondrial enlargement, cristae dissoln., and lipid droplets. Lipid droplets found in the heart, diaphragm, biceps, and liver were sufficient to identify FIAU-treated WC (each). Widespread mitochondrial damage to many tissues resulted from chronic FIAU treatment and occurred irresp. of CH. It manifested with mtDNA depletion, intracytoplasmic lipid droplets, and destroyed mitochondrial cristae. Defective mtDNA replication with mtDNA depletion seems central to the subcellular pathophysiol. of altered energy metab. and multiorgan failure in FIAU toxicity.
- 13Lebrecht, D., Vargas-Infante, Y. A., Setzer, B., Kirschner, J., and Walker, U. A. (2007) Uridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in mice. Hepatology 45, 72– 79, DOI: 10.1002/hep.2149013https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28jlsFGguw%253D%253D&md5=380ea7d7d80484d493c622d08c40980aUridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in miceLebrecht Dirk; Vargas-Infante Yetlanezi A; Setzer Bernhard; Kirschner Janbernd; Walker Ulrich AHepatology (Baltimore, Md.) (2007), 45 (1), 72-9 ISSN:0270-9139.UNLABELLED: Zalcitabine is an antiretroviral nucleoside analogue that exhibits long-term toxicity to hepatocytes by interfering with the replication of mitochondrial DNA (mtDNA). Uridine antagonizes this effect in vitro. In the present study we investigate the mechanisms of zalcitabine-induced hepatotoxicity in mice and explore therapeutic outcomes with oral uridine supplementation. BalbC mice (7 weeks of age, 9 mice in each group) were fed 0.36 mg/kg/d of zalcitabine (corresponding to human dosing adapted for body surface), or 13 mg/kg/d of zalcitabine. Both zalcitabine groups were treated with or without Mitocnol (0.34 g/kg/d), a dietary supplement with high bioavailability of uridine. Liver histology and mitochondrial functions were assessed after 15 weeks. One mouse exposed to high dose zalcitabine died at 19 weeks of age. Zalcitabine induced a dose dependent microvesicular steatohepatitis with abundant mitochondria. The organelles were enlarged and contained disrupted cristae. Terminal transferase dUTP nick end labeling (TUNEL) assays showed frequent hepatocyte apoptosis. mtDNA was depleted in liver tissue, cytochrome c-oxidase but not succinate dehydrogenase activities were decreased, superoxide and malondialdehyde were elevated. The expression of COX I, an mtDNA-encoded respiratory chain subunit was reduced, whereas COX IV, a nucleus-encoded subunit was preserved. Uridine supplementation normalized or attenuated all toxic abnormalities in both zalcitabine groups, but had no effects when given without zalcitabine. Uridine supplementation was without apparent side effects. CONCLUSION: Zalcitabine induces mtDNA-depletion in murine liver with consequent respiratory chain dysfunction, up-regulated synthesis of reactive oxygen species and microvesicular steatohepatitis. Uridine supplementation attenuates this mitochondrial hepatotoxicity without apparent intrinsic effects.
- 14Bailey, C. M., Kasiviswanathan, R., Copeland, W. C., and Anderson, K. S. (2009) R964C mutation of DNA polymerase gamma imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activity. Antimicrob. Agents Chemother. 53, 2610– 2612, DOI: 10.1128/AAC.01659-0814https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntFGks7g%253D&md5=2512d3efd67530b0d481d773b1571a7dR964C mutation of DNA polymerase γ imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activityBailey, Christopher M.; Kasiviswanathan, Rajesh; Copeland, William C.; Anderson, Karen S.Antimicrobial Agents and Chemotherapy (2009), 53 (6), 2610-2612CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The R964C mutation of human DNA polymerase γ was recently linked to stavudine (d4T)-mediated mitochondrial toxicity. We utilized pre-steady-state kinetics to det. the effect of this mutation on incorporation of natural substrate dTTP and the active metabolite of d4T (d4TTP). The R964C polymerase γ holoenzyme demonstrated a 33% decrease in dTTP incorporation efficiency and a threefold-lower d4TTP discrimination relative to that of the wild-type polymerase γ, providing a mechanistic basis for genetic predisposition to nucleoside reverse transcriptase inhibitor toxicity.
- 15Fromenty, B., Fisch, C., Berson, A., Lettéron, P., Larrey, D., and Pessayre, D. (1990) Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex II. J. Pharmacol. Exp. Ther. 255, 1377– 138415https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXpsVyksA%253D%253D&md5=deb74f7f13fd3c61efb10feea19c3103Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex IIFromenty, Bernard; Fisch, Cecile; Berson, Alain; Letteron, Philippe; Larrey, Dominique; Pessayre, DominiqueJournal of Pharmacology and Experimental Therapeutics (1990), 255 (3), 1377-84CODEN: JPETAB; ISSN:0022-3565.The effects of amiodarone on the respiration of isolated mouse liver mitochondria were detd. Amiodarone (200 μM) had a biphasic effect on state 4 respiration supported by either glutamate plus malate or succinate. Initially, the respiratory rate was increased. This stimulatory effect was not prevented by oligomycin (an inhibitor of ATP synthase). It was assocd. with marked accumulation of amiodarone in the mitochondria, and with collapse of the mitochondrial membrane potential. This initial uncoupling effect was followed by a progressive decrease in the state 4 respiration rate, leading eventually to marked inhibition. Preincubation for 5 min with amiodarone (200 μM) also decreased markedly ADP-stimulated (state 3) respiration, ATP prodn. and dinitrophenol-stimulated (uncoupled) respiration supported by glutamate plus malate (which donate electrons to complex I), and respiration supported by succinate (which donate electrons to complex II), but did not affect respiration supported by duroquinol (donating electrons to complex III) or by ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine (donating electrons to cytochrome c). Preincubation with amiodarone (150-200 μM) decreased markedly respiration mediated by fatty acids of various chain length and respiration mediated by citrate, a tricarboxylic acid cycle substrate. Thus, amiodarone has a dual effect on mitochondrial respiration. The initial uncoupling effect is probably due to the entry of protonated amiodarone, releasing a proton in the matrix. Accumulation of amiodarone soon leads to inhibition of the respiratory chain at the levels of complex I and complex II and to decreased ATP formation.
- 16Felser, A., Blum, K., Lindinger, P. W., Bouitbir, J., and Krähenbühl, S. (2013) Mechanisms of hepatocellular toxicity associated with dronedarone-a comparison to amiodarone. Toxicol. Sci. 131, 480– 490, DOI: 10.1093/toxsci/kfs29816https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFent7w%253D&md5=e7151b62d993396ac9832b40160c262cMechanisms of Hepatocellular Toxicity Associated with Dronedarone-A Comparison to AmiodaroneFelser, Andrea; Blum, Kim; Lindinger, Peter W.; Bouitbir, Jamal; Krahenbuhl, StephanToxicological Sciences (2013), 131 (2), 480-490CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50μM, resp. The cellular ATP content started to decrease at 20μM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concns. of ~10μM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was obsd. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial β-oxidn. at 10μM and amiodarone at 20μM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of β-oxidn. both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo.
- 17Deschamps, D., DeBeco, V., Fisch, C., Fromenty, B., Guillouzo, A., and Pessayre, D. (1994) Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions. Hepatology 19, 948– 961, DOI: 10.1002/hep.184019042217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXkvF2gtbo%253D&md5=311e193271275d0bf108cea809e94abeInhibition by perhexiline of oxidative phosphorylation and the β-oxidation of fatty acids: Possible role in pseudoalcoholic liver lesionsDeschamps, Dominique; DeBeco, Virginie; Fisch, Cecile; Fromenty, Bernard; Guillouzo, Andre; Pessayre, DominiqueHepatology (Philadelphia, PA, United States) (1994), 19 (4), 948-61CODEN: HPTLD9; ISSN:0270-9139.In an attempt to better understand the mechanisms for pseudoalcoholic liver lesions in human beings, the authors detd. the effects of perhexiline on mitochondrial functions in mice and rats. A first series of studies suggested that protonated perhexiline entered mouse mitochondria along the mitochondrial membrane potential. Release of a proton in the mitochondrial matrix led to uncoupling of oxidative phosphorylation, and accumulation of perhexiline inhibited complexes I and II of the respiratory chain, decreased ATP formation in vitro and decreased the mitochondrial β-oxidn. of long-, medium- and short-chain fatty acids in vitro and in vivo in mice. In cultured rat hepatocytes, exposure for 24 h to 25 μmol/L perhexiline markedly decreased hepatocellular ATP and cell viability. Exposure to 5 μmol/L perhexiline did not modify ATP and viability but decreased the β-oxidn. of palmitic acid uniformly labeled with carbon 14 by 38%, increased hepatocyte triglyceride levels by 98% and produced microvesicular steatosis after 72 h of culture. The authors conclude that perhexiline is concd. inside mitochondria, where it inhibits both oxidative phosphorylation and the mitochondrial β-oxidn. of fatty acids. These effects may contribute to the development of necrosis, steatosis and possibly certain other pseudoalcoholic liver lesions in human beings.
- 18Berson, A., Fau, D., Fornacciari, R., Degove-Goddard, P., Sutton, A., Descatoire, V., Haouzi, D., Lettéron, P., Moreau, A., Feldmann, G., and Pessayre, D. (2001) Mechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activation. J. Hepatol. 34, 261– 269, DOI: 10.1016/S0168-8278(00)00050-718https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXislCksLY%253D&md5=ea9538e36c230f4a7e41e614848f289dMechanisms for experimental buprenorphine hepatotoxicity: major role of mitochondrial dysfunction versus metabolic activationBerson, Alain; Fau, Daniel; Fornacciari, Roxane; Degove-Goddard, Pamela; Sutton, Angela; Descatoire, Veronique; Haouzi, Delphine; Letteron, Philippe; Moreau, Alain; Feldmann, Gerard; Pessayre, DominiqueJournal of Hepatology (2001), 34 (2), 261-269CODEN: JOHEEC; ISSN:0168-8278. (Elsevier Science Ltd.)Background/Aims: Although sublingual buprenorphine is safely used as a substitution drug in heroin addicts, large over doses or i.v. misuse may cause hepatitis. Buprenorphine is N-dealkylated to norbuprenorphine by CYP3A. Methods: We investigated the mitochondrial effects and metabolic activation of buprenorphine in isolated rat liver mitochondria and microsomes, and its toxicity in isolated rat hepatocytes and treated mice. Results: Whereas norbuprenorphine had few mitochondrial effects, buprenorphine (25-200 μM) concd. in mitochondria, collapsed the membrane potential, inhibited β-oxidn., and both uncoupled and inhibited respiration in rat liver mitochondria. Both buprenorphine and norbuprenorphine (200 μM) underwent CYP3A-mediated covalent binding to rat liver microsomal proteins and both caused moderate glutathione depletion and increased cell calcium in isolated rat hepatocytes, but only buprenorphine also depleted cell ATP and caused necrotic cell death. Four hours after buprenorphine administration to mice (100 nmol/g body wt.), hepatic glutathione was unchanged, while ATP was decreased and serum transaminase increased. This transaminase increase was attenuated by a CYP3A inducer and aggravated by a CYP3A inhibitor. Conclusions: Both buprenorphine and norbuprenorphine undergo metabolic activation, but only buprenorphine impairs mitochondrial respiration and ATP formation. The hepatotoxicity of high concns. or doses of buprenorphine is mainly related to its mitochondrial effects.
- 19Wood, D. M., Alsahaf, H., Streete, P., Dargan, P. I., and Jones, A. L. (2005) Fatality after deliberate ingestion of the pesticide rotenone: a case report. Crit. Care 9, R280– R284, DOI: 10.1186/cc3528There is no corresponding record for this reference.
- 20Jiang, X. W., Qiao, L., Feng, X. X., Liu, L., Wei, Q. W., Wang, X. W., and Yu, W. H. (2017) Rotenone induces nephrotoxicity in rats: oxidative damage and apoptosis. Toxicol. Mech. Methods 27, 528– 536, DOI: 10.1080/15376516.2017.133355320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVeqs7bM&md5=ef069e6896d2907dd5b72ba572597c18Rotenone induces nephrotoxicity in rats: oxidative damage and apoptosisJiang, Xiao-Wen; Qiao, Lu; Feng, Xin-xin; Liu, Lin; Wei, Qing-Wei; Wang, Xue-Wei; Yu, Wen-HuiToxicology Mechanisms and Methods (2017), 27 (7), 528-536CODEN: TMMOCP; ISSN:1537-6516. (Taylor & Francis Ltd.)Previous studies have examd. rotenone toxicity on the human central nervous system, esp. in the pathogenesis of Parkinson's disease, but few have investigated the effects of rotenone on the kidney. Here, rotenone-induced nephrotoxicity was evaluated by detg. morphol., biochem., oxidative stress-related, and apoptotic factor alterations in rat renal tissue. Morphol. and biochem. analyzes showed that rotenone administration to rats damaged renal tissue. Western blot results revealed that rotenone-induced oxidative damage, causing overprodn. of glutathione, malonaldehyde, and reactive oxygen species (ROS), and inhibiting superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. Rotenone also decreased the mitochondrial membrane potential and increased voltage-dependent anion channel (VDAC), caspase-3, and caspase-9 protein levels, indicating an assocn. of apoptosis with renal damage. Our results suggest that glutathione, malonaldehyde, and ROS may be signals of rotenone-induced oxidative damage, and that the mitochondrial pathway plays a key role in apoptosis of renal cells following rotenone administration.
- 21Watkins, R. C., Hambrick, E. L., Benjamin, G., and Chavda, S. N. (1990) Isoniazid toxicity presenting as seizures and metabolic acidosis. J. Natl. Med. Assoc. 82, 57– 6421https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3c7ls1Cgug%253D%253D&md5=0460cf5e3eb69deb36f24b1df514e839Isoniazid toxicity presenting as seizures and metabolic acidosisWatkins R C; Hambrick E L; Benjamin G; Chavda S NJournal of the National Medical Association (1990), 82 (1), 57, 62, 64 ISSN:0027-9684.The presenting signs and symptoms of isoniazid toxicity are discussed, with a review of the complications and management of this metabolic encephalopathy with B6 pyridoxine. This study supports previous studies in finding that ingestion of more than 80 mg/kg body weight produces severe central nervous system symptoms that are rapidly reversed with intravenous administration of pyridoxine.
- 22Gokhale, Y. A., Vaidya, M. S., Mehta, A. D., and Rathod, N. N. (2009) Isoniazid toxicity presenting as status epilepticus and severe metabolic acidosis. J. Assoc. Physicians India 57, 70– 7122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnisFKgsA%253D%253D&md5=4f87235c860ebb38e2e93ef70b382e71Isoniazid toxicity presenting as status epilepticus and severe metabolic acidosisGokhale Yojana A; Vaidya Meghna S; Mehta A D; Rathod N NThe Journal of the Association of Physicians of India (2009), 57 (), 70-1 ISSN:0004-5772.Isoniazid (INH) is an integral component of treatment of tuberculosis. An acute overdose is potentially fatal and is characterized by the clinical triad of repetitive seizures unresponsive to the usual anticonvulsants, metabolic acidosis with a high anion gap and coma. The diagnosis of INH overdose should be considered in any patient who presents to emergency medical services (EMS) with the triad. We report a patient presenting with multiple generalised tonic clonic (GTC) convulsions with severe metabolic acidosis as a manifestation of INH toxicity.
- 23Isenberg, J. S. and Klaunig, J. E. (2000) Role of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cells. Toxicol. Sci. 53, 340– 351, DOI: 10.1093/toxsci/53.2.34023https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhtF2ksL4%253D&md5=3ee6fbf89560bc157a0f28202c7d148aRole of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cellsIsenberg, Jason S.; Klaunig, James E.Toxicological Sciences (2000), 53 (2), 340-351CODEN: TOSCF2; ISSN:1096-6080. (Oxford University Press)Rotenone inhibits spontaneously and chem. induced hepatic tumorigenesis in rodents through the induction of apoptosis. However, the mechanism for the induction of apoptosis by rotenone has not been defined. Mitochondrial dysfunction, in particular the induction of the mitochondrial membrane permeability transition (MPT), has been implicated in the cascade of events involved in the induction of apoptosis. Inhibition of the mitochondrial electron-transport chain reduces the mitochondrial transmembrane potential (Δψm), which may induce the formation of the mitochondrial permeability transition pore and the subsequent MPT. Fluorescent microscopy of Hoechst 33258-stained WB-F344 cells, a rat-liver cell line, was utilized to examine the effect of the mitochondrial respiratory chain inhibitor, rotenone (0.5-5 μM), atractyloside (5-10 μM), and cyclosporin A (2.5-10 μM) on apoptosis. A time- and concn.-dependent increase in liver cell apoptosis was obsd. following treatment with rotenone and atractyloside (11.7- and 7.7-fold, resp., over solvent control). Cotreatment with 7.5- and 10 μM-cyclosporin A for 12 h inhibited the apoptogenicity of 5-μM rotenone treatment. A similar effect was obsd. following cyclosporin A cotreatment with atractyloside. Rotenone induced a rapid increase in apoptosis (within 20 min of treatment). By 2 h of treatment, the morphol. appearance of apoptosis was similar to that obsd. in cultures treated continuously with rotenone for 12 h. Inhibition studies demonstrated that cyclosporin A prevented apoptosis if the exposure to it occurred prior to the 20-min threshold necessary to induce apoptosis by rotenone. Mitochondrial function was examd. by staining with the mitochondrial membrane potential (Δψm)-sensitive fluorochrome, MitoTracker Red (CMXRos) and confirmed utilizing cytofluorometric anal. of DiOC6-stained cells. Rotenone (5.0-μM) and atractyloside (5.0-μM) reduced the percent of CMXRos or DiOC6-pos. (Δψm-pos.) liver cells within 15 min and throughout the duration of the study (6 h) to approx. 65-80% and 50-80% of control. However, co-treatment with concns. of cyclosporin A that inhibited the apoptogenicity of rotenone and atractyloside prevented the rotenone- and atractyloside-induced redn. of the Δψm. Therefore, the apoptogenic effect of rotenone and atractyloside appears to occur rapidly (within 20 min) and is irreversible once mitochondrial damage occurs. The inhibition of the rotenone- and atractyloside-induced apoptosis and mitochondrial dysfunction by cyclosporin A suggests the MPT may be involved in the induction of apoptosis by rotenone.
- 24Mann, A., Pelz, T., Rennert, K., Mosig, A., Decker, M., and Lupp, A. (2017) Evaluation of HepaRG cells for the assessment of indirect drug-induced hepatotoxicity using INH as a model substance. Hum. Cell 30, 267– 278, DOI: 10.1007/s13577-017-0175-924https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotVOlur8%253D&md5=a8360bdfb4378e3bb4c68ea10d18a59eEvaluation of HepaRG cells for the assessment of indirect drug-induced hepatotoxicity using INH as a model substanceMann, Anika; Pelz, Thomas; Rennert, Knut; Mosig, Alexander; Decker, Michael; Lupp, AmelieHuman Cell (2017), 30 (4), 267-278CODEN: HUCEE7; ISSN:1749-0774. (Springer)HepaRG cells are widely used as an in vitro model to assess drug-induced hepatotoxicity. However, only few studies exist so far regarding their suitability to detect the effects of drugs requiring a preceding activation via the cytochrome P 450 (CYP) system. A prototypic substance is the anti-tuberculosis agent INH, which is metabolized into N-acetylhydrazine, which then triggers hepatotoxicity. Therefore, the aim of the present study was to test if this effect can also be detected in HepaRG cells and if it can be counteracted by the known hepatoprotectant silibinin. For this purpose, differentiated HepaRG cells were treated with increasing concns. of INH (0.1-100 mM) or 10 mM INH plus escalating concns. of silibinin (1-100 μM). After 48 h of treatment, cell morphol. and parameters indicating cell vitality, oxidative stress, and liver cell function were assessed. High concns. of INH led to severe histopathol. changes, reduced cell vitality and glutathione content, increased LDH and ASAT release into the medium, enhanced lipid peroxidn., and elevated cleaved caspase-3 expression. Addnl., glycogen depletion and reduced biotransformation capacity were seen at high INH concns., whereas at low concns. an induction of biotransformation enzymes was noticed. Silibinin caused clear-cut protective effects, but with few parameters INH toxicity was even aggravated, most probably due to increased metabolization of INH into its toxic metabolite. In conclusion, HepaRG cells are excellently suited to evaluate the effects of substances requiring prior toxification via the CYP system, such as INH. They addnl. enable the identification of complex substance interactions.
- 25Catta-Preta, M., Mendonca, L. S., Fraulob-Aquino, J., Aguila, M. B., and Mandarim-de-Lacerda, C. A. (2011) A critical analysis of three quantitative methods of assessment of hepatic steatosis in liver biopsies. Virchows Arch. 459, 477– 485, DOI: 10.1007/s00428-011-1147-125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3Mblt1CjtQ%253D%253D&md5=1a3a1da42048b5d842c5238efe63fc88A critical analysis of three quantitative methods of assessment of hepatic steatosis in liver biopsiesCatta-Preta Mariana; Mendonca Leonardo Souza; Fraulob-Aquino Julio; Aguila Marcia Barbosa; Mandarim-de-Lacerda Carlos AlbertoVirchows Archiv : an international journal of pathology (2011), 459 (5), 477-85 ISSN:.The issue of adequately quantitatively evaluating hepatic steatosis is still unresolved. Therefore, we compared three methods of quantitative assessment. Two groups of mice (n = 10 each) were fed standard chow (10% fat, SC group) or a high-fat diet (60% fat, HF group) for 16 weeks, and hepatic triglyceride (HT) and liver tissue were then studied. Paraplast-embedded tissues stained by hematoxylin and eosin (H-E) were compared to frozen sections stained by Oil Red-O (ORO). In addition, the volume density of steatosis (Vv[steatosis, liver]) was measured by point counting (P-C, sections H-E or ORO) or by image analysis (I-A, sections ORO). HT was significantly higher in the HF group (104% greater, P = 0.0004) than in the SC group. With P-C and H-E, Vv[steatosis, liver] was 4.80 ± 0.90% in the SC group and 33.50 ± 3.17% in the HF group (600% greater, P < 0.0001). With P-C and ORO, Vv[steatosis, liver] was 4.86 ± 0.89% in the SC group and 25.21 ± 1.27% in the HF group (420% greater, P < 0.0001). With I-A and ORO, Vv[steatosis, liver] was 4.17 ± 0.85% in the SC group and 23.35 ± 1.58% in the HF group (460% greater, P < 0.0001). Correlations between Vv[steatosis, liver] and HT were strong and significant in all methods. In conclusion, all methods were appropriate and reproducible. In P-C and H-E, there is a slight overestimation of steatosis in the HF animals in comparison to frozen sections and ORO; in frozen sections, differences between P-C and I-A are insignificant.
- 26Massart, J., Begriche, K., Buron, N., Porceddu, M., Borgne-Sanchez, A., and Fromenty, B. (2013) Drug-induced inhibition of mitochondrial fatty acid oxidation and steatosis. Curr. Pathobiol. Rep. 1, 147– 157, DOI: 10.1007/s40139-013-0022-yThere is no corresponding record for this reference.
- 27Tandra, S., Yeh, M. M., Brunt, E. M., Vuppalanchi, R., Cummings, O. W., Ünalp-Arida, A., Wilson, L. A., and Chalasani, N. (2011) Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease. J. Hepatol. 55, 654– 659, DOI: 10.1016/j.jhep.2010.11.02127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MfmslShtw%253D%253D&md5=fd55ac974d2b6a4b3d5495e480f530a9Presence and significance of microvesicular steatosis in nonalcoholic fatty liver diseaseTandra Sweta; Vuppalanchi Raj; Cummings Oscar W; Yeh Matthew M; Brunt Elizabeth M; Unalp-Arida Aynur; Wilson Laura A; Chalasani NagaJournal of hepatology (2011), 55 (3), 654-659 ISSN:.BACKGROUND & AIMS: Liver biopsies from patients with nonalcoholic fatty liver disease (NAFLD) sometimes exhibit non-zonal aggregates of hepatocytes with microvesicular steatosis, but its prevalence and significance are unclear. In this study, we have evaluated the frequency of microvesicular steatosis and assessed its association with histological markers of disease severity in a large sample of NAFLD liver biopsies. METHODS: Liver biopsies from a large cohort of adults who participated in two studies conducted by the NASH Clinical Research Network (NASH CRN) were included in this cross-sectional study. Liver histology was assessed centrally and various histological features scored in a systematic fashion. The relationship between microvesicular steatosis and various histological features that characterize NAFLD was tested by multiple logistic regression, after controlling for age, gender, race, body mass index, and diabetes. RESULTS: Among 1022 liver biopsies included, 102 (10%) had microvesicular steatosis. No demographic differences were noted between patients with or without microvesicular steatosis. The presence of microvesicular steatosis was associated with higher grades of steatosis (p<0.001), ballooning cell injury (p<0.001), presence of Mallory-Denk bodies (p<0.007), presence of megamitochondria (p<0.0001), higher NAS scores (p<0.0001), more advanced fibrosis (p<0.0001), and diagnosis of borderline or definite NASH (p<0.0001). CONCLUSIONS: Microvesicular steatosis correlates with more advanced histology of NAFLD. Longitudinal studies are needed to address the role of microvesicular steatosis in mediating cellular injury and disease progression in NAFLD.
- 28Amacher, D. E. (2012) The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin. Drug Metab. Toxicol. 8, 335– 347, DOI: 10.1517/17425255.2012.65804128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisFWitLw%253D&md5=ff76f002fd099276dad9bd5e742a8902The primary role of hepatic metabolism in idiosyncratic drug-induced liver injuryAmacher, David E.Expert Opinion on Drug Metabolism & Toxicology (2012), 8 (3), 335-347CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. Introduction: Idiosyncratic drug-induced liver injury (DILI) is a rare, serious and sometimes fatal condition that lacks an effective clin. countermeasure. Polymorphisms of bioactivation/toxification pathways via the Phase I drug-metabolizing enzymes, Phase II detoxification reactions and Phase III excretion/transport, together with immunol. factors, are predisposing factors for some DILI.Areas covered: This review focuses on the seminal role of hepatic drug metab. in the idiosyncratic toxicity response and the potential role of genetic polymorphisms in specific drug-metabolizing enzymes or transporters. Furthermore, the article looks at recent developments for the assessment of those mechanisms, in order to avoid them in novel drug candidates that are still under development. Examples of proposed or confirmed metabolic mechanisms from the current literature for marketed or previously marketed drugs are summarized in detail. The contributions of Phase I, II and III and other enzymic pathways in the idiosyncratic response are reviewed with particular emphasis on gene polymorphisms that might explain why some individuals respond in an aberrant manner.Expert opinion: Toxicologists continue to focus their efforts to define the idiosyncratic response at the biochem. and mol. levels. This has resulted in the development of some early drug screening tools based on such characteristics as the daily dose, metabolite covalent binding and polymorphisms in drug-metabolizing enzymes. While it will take years to fully assess the impact of these recently developed assessment tools, research on genetically based differences in hepatic metabolic pathways will continue, aided by the establishment of DILI registries for improved patient access.
- 29McGill, M. R. and Jaeschke, H. (2019) Animal models of drug-induced liver injury. Biochim. Biophys. Acta, Mol. Basis Dis. 1865, 1031– 1039, DOI: 10.1016/j.bbadis.2018.08.03729https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1OrsLrF&md5=8f73f53aa566cd81f23521a324fa1ae1Animal models of drug-induced liver injuryMcGill, Mitchell R.; Jaeschke, HartmutBiochimica et Biophysica Acta, Molecular Basis of Disease (2019), 1865 (5), 1031-1039CODEN: BBADEX; ISSN:0925-4439. (Elsevier B.V.)A review. Drug-induced liver injury (DILI) presents unique challenges for consumers, clinicians, and regulators. It is the most common cause of acute liver failure in the US. It is also one of the most common reasons for termination of new drugs during pre-clin. testing and withdrawal of new drugs post-marketing. DILI is generally divided into two forms: intrinsic and idiosyncratic. Many of the challenges with DILI are due in large part to poor understanding of the mechanisms of toxicity. Although useful models of intrinsic DILI are available, they are frequently misused. Modeling idiosyncratic DILI presents greater challenges, but promising new models have recently been developed. The purpose of this manuscript is to provide a crit. review of the most popular animal models of DILI, and to discuss the future of DILI research.
- 30Church, R. J., Wu, H., Mosedale, M., Sumner, S. J., Pathmasiri, W., Kurtz, C. L., Pletcher, M. T., Eaddy, J. S., Pandher, K., Singer, M., Batheja, A., Watkins, P. B., Adkins, K., and Harrill, A. H. (2014) A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis. Toxicol. Sci. 140, 481– 492, DOI: 10.1093/toxsci/kfu09430https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1ygtrrL&md5=2c2c6fce621e868d096b5c373fb5ae78A Systems Biology Approach Utilizing a Mouse Diversity Panel Identifies Genetic Differences Influencing Isoniazid-Induced Microvesicular SteatosisChurch, Rachel J.; Wu, Hong; Mosedale, Merrie; Sumner, Susan J.; Pathmasiri, Wimal; Kurtz, Catherine L.; Pletcher, Mathew T.; Eaddy, John S.; Pandher, Karamjeet; Singer, Monica; Batheja, Ameesha; Watkins, Paul B.; Adkins, Karissa; Harrill, Alison H.Toxicological Sciences (2014), 140 (2), 481-492CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)Isoniazid (INH), the mainstay therapeutic for tuberculosis infection, has been assocd. with rare but serious hepatotoxicity in the clinic. However, the mechanisms underlying inter-individual variability in the response to this drug have remained elusive. A genetically diverse mouse population model in combination with a systems biol. approach was utilized to identify transcriptional changes, INH-responsive metabolites, and gene variants that contribute to the liver response in genetically sensitive individuals. Sensitive mouse strains developed severe microvesicular steatosis compared with corresponding vehicle control mice following 3 days of oral treatment with INH. Genes involved in mitochondrial dysfunction were enriched among liver transcripts altered with INH treatment. Those assocd. with INH treatment and susceptibility to INH-induced steatosis in the liver included apolipoprotein A-IV, lysosomal-assocd. membrane protein 1, and choline phosphotransferase 1. These alterations were accompanied by metabolomic changes including reduced levels of glutathione and the choline metabolites betaine and phosphocholine, suggesting that oxidative stress and reduced lipid export may addnl. contribute to INH-induced steatosis. Finally, genome-wide assocn. mapping revealed that polymorphisms in perilipin 2 were linked to increased triglyceride levels following INH treatment, implicating a role for inter-individual differences in lipid packaging in the susceptibility to INH-induced steatosis. Taken together, our data suggest that INH-induced steatosis is caused by not one, but multiple events involving lipid retention in the livers of genetically sensitive individuals. This work also highlights the value of using a mouse diversity panel to investigate drug-induced responses across a diverse population.
- 31Stewart, J. D., Horvath, R., Baruffini, E., Ferrero, I., Bulst, S., Watkins, P. B., Fontana, R. J., Day, C. P., and Chinnery, P. F. (2010) Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology 52, 1791– 1796, DOI: 10.1002/hep.2389131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFOnsrvE&md5=45eac0bcd5428d1be9cae5b888c69febPolymerase γ gene POLG Determines the Risk of Sodium Valproate-Induced Liver ToxicityStewart, Joanna D.; Horvarth, Rita; Baruffin, Enrico; Ferrero, Iliana; Bulst, Stefanie; Watkins, Paul B.; Fontana, Robert J.; Day, Christopher P.; Chinnery, PatrickHepatology (Hoboken, NJ, United States) (2010), 52 (5), 1791-1796CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)Sodium valproate (VPA) is widely used throughout the world to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy. VPA toxicity is an uncommon but potentially fatal cause of idiosyncratic liver injury. Rare mutations in POLG, which codes for the mitochondrial DNA polymerase γ (poly), cause Aplers-Huttenlocher syndrome (AHS). AHS is a neurometabolic disorder assocd. with an increased risk of developing fatal VPA hepatoxicity. We therefore set out to det. whether common genetic variants in POLG explain why some otherwise healthy individuals develop VPA hepatotoxicity. We carried out a prospective study of subjects enrolled in the Drug Induced Liver Injury Network (DILIN) from 2004 to 2008 through five US centers. POLG was sequenced and the functional consequences of VPA and novel POLG variants were evaluated in primary human cell lines and the yeast model system Saccharomyces cerevisiae. Heterozygous genetic variation in POLG was strongly assocd. with VPA- induced liver toxicity (odds ratio = 23.6, 95% confidence interval [CI] = 8.4-65.8, p = 5.1 × 10-7). This was principally due to the p.Q1236H substitution which compromised poly function in yeast. Therapeutic does of VPA inhibited human cellular proliferation and high doses caused nanopoptotic cell death, which was not mediated through mitochondrial DNA Depletion, mutation, or a defect of fatty acid metab. Conclusion: These findings implicate impaired liver regeneration in VPA toxicity and show that prospective genetic testing of POLG will identify individuals at high risk of this potentially fatal consequence of treatment.
- 32Lucena, M. I., García-Martín, E., Andrade, R. J., Martínez, C., Stephens, C., Ruiz, J. D., Ulzurrun, E., Fernandez, M. C., Romero-Gomez, M., Castiella, A., Planas, R., Durán, J. A., De Dios, A. M., Guarner, C., Soriano, G., Borraz, Y., and Agundez, J. A. (2010) Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology 52, 303– 312, DOI: 10.1002/hep.2366832https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpsFShtbc%253D&md5=72eb0f4a53f44f51e1604e8a991fb47bMitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injuryLucena, M. Isabel; Garcia-Martin, Elena; Andrade, Raul J.; Martinez, Carmen; Stephens, Camilla; Ruiz, Jhon D.; Ulzurrun, Eugenia; Fernandez, M. Carmen; Romero-Gomez, Manuel; Castiella, Augustin; Planas, Ramon; Duran, Jose Antonio; De Dios, Ana Melcon; Guarner, Carlos; Soriano, German; Borraz, Yolanda; Agundez, Jose A. G.Hepatology (Hoboken, NJ, United States) (2010), 52 (1), 303-312CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible assocns. between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2 Val16Ala) and glutathione peroxidase (GPX1 Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex- and age-matched controls were analyzed. The SOD2 and GPX1 genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quant. polymerase chain reaction, resp. The statistical power to detect the effect of variant alleles with the obsd. odds ratio (OR) was 98.2% and 99.7% for bilateral assocn. of SOD2 and GPX1, resp. The SOD2 Ala/Ala genotype was assocd. with cholestatic/mixed damage (OR = 2.3; 95% confidence interval [CI] = 1.4-3.8; cor. P [Pc] = 0.0058), whereas the GPX1 Leu/Leu genotype was assocd. with cholestatic injury (OR = 5.1; 95%CI = 1.6-16.0; Pc = 0.0112). The presence of two or more combined risk alleles (SOD2 Ala and GPX1 Leu) was more frequent in DILI patients (OR = 2.1; 95%CI = 1.4-3.0; Pc = 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the SOD2 Ala/Ala genotype (OR = 3.6; 95%CI = 1.4-9.3; Pc = 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR = 3.0; 95%CI = 1.7-5.5; Pc = 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR = 16.0; 95%CI = 1.8-146.1; Pc = 0.009). Patients homozygous for the SOD2 Ala allele and the GPX1 Leu allele are at higher risk of developing cholestatic DILI. SOD2 Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates.
- 33Borgne-Sanchez, A., and Fromenty, B. (2018) Mitochondrial dysfunction in drug-induced liver injury. In Drug-Induced Mitochondrial Dysfunction: Progress Towards the Clinics (Will, Y., and Dykens, J. A., Eds.) 2nd ed., pp 49– 72, John Wiley & Sons, Hoboken.There is no corresponding record for this reference.