ACS Publications. Most Trusted. Most Cited. Most Read
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, 2019
My Activity
  • Free to Read
Letters to the Editor

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, 2019
Click to copy article linkArticle link copied!

  • Bernard Fromenty
    Bernard Fromenty
    INSERM, Université de Rennes, INRAE, Nutrition, Metabolisms, and Cancer (NuMeCan) Institut, UMR_A 1341, UMR_S 1241, F-35000 Rennes, France
Open PDF

Chemical Research in Toxicology

Cite this: Chem. Res. Toxicol. 2020, 33, 1, 2–4
Click to copy citationCitation copied!
https://doi.org/10.1021/acs.chemrestox.9b00416
Published December 10, 2019

Copyright © 2019 American Chemical Society. This publication is available under these Terms of Use.

This publication is licensed for personal use by The American Chemical Society.

Copyright © 2019 American Chemical Society

SPECIAL ISSUE

This article is part of the Drug Metabolism and Toxicology special issue.

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.

Author Information

Click to copy section linkSection link copied!

    • Author
      • Bernard Fromenty - INSERM, Université de Rennes, INRAE, Nutrition, Metabolisms, and Cancer (NuMeCan) Institut, UMR_A 1341, UMR_S 1241, F-35000 Rennes, France

    Acknowledgments

    Click to copy section linkSection link copied!

    I am very grateful to Dr Julie Massart for her critical reading of this letter.

    References

    Click to copy section linkSection link copied!

    This article references 33 other publications.

    1. 1
      Labbe, 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, 335353,  DOI: 10.1111/j.1472-8206.2008.00608.x
    2. 2
      Cho, T. and Uetrecht, J. (2017) How reactive metabolites induce an immune response that sometimes leads to an idiosyncratic drug reaction. Chem. Res. Toxicol. 30, 295314,  DOI: 10.1021/acs.chemrestox.6b00357
    3. 3
      Porceddu, 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, 332345,  DOI: 10.1093/toxsci/KFS197
    4. 4
      Ramachandran, 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, 75100,  DOI: 10.18053/jctres.04.201801.005
    5. 5
      Begriche, 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, 773794,  DOI: 10.1016/j.jhep.2010.11.006
    6. 6
      Cho, 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, 14231431,  DOI: 10.1021/acs.chemrestox.9b00116
    7. 7
      Fromenty, B. and Pessayre, D. (1995) Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101154,  DOI: 10.1016/0163-7258(95)00012-6
    8. 8
      McKenzie, 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, 10991105,  DOI: 10.1056/NEJM199510263331702
    9. 9
      Mak, 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, 383392,  DOI: 10.1517/14740338.2016.1139573
    10. 10
      Igoudjil, 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, 273292,  DOI: 10.2174/187152106777697871
    11. 11
      Wang, 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, 11801187,  DOI: 10.1016/j.ajpath.2012.12.033
    12. 12
      Lewis, 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, 7787
    13. 13
      Lebrecht, 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, 7279,  DOI: 10.1002/hep.21490
    14. 14
      Bailey, 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, 26102612,  DOI: 10.1128/AAC.01659-08
    15. 15
      Fromenty, 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, 13771384
    16. 16
      Felser, 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, 480490,  DOI: 10.1093/toxsci/kfs298
    17. 17
      Deschamps, 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, 948961,  DOI: 10.1002/hep.1840190422
    18. 18
      Berson, 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, 261269,  DOI: 10.1016/S0168-8278(00)00050-7
    19. 19
      Wood, 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, R280R284,  DOI: 10.1186/cc3528
    20. 20
      Jiang, 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, 528536,  DOI: 10.1080/15376516.2017.1333553
    21. 21
      Watkins, 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, 5764
    22. 22
      Gokhale, 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, 7071
    23. 23
      Isenberg, 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, 340351,  DOI: 10.1093/toxsci/53.2.340
    24. 24
      Mann, 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, 267278,  DOI: 10.1007/s13577-017-0175-9
    25. 25
      Catta-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, 477485,  DOI: 10.1007/s00428-011-1147-1
    26. 26
      Massart, 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, 147157,  DOI: 10.1007/s40139-013-0022-y
    27. 27
      Tandra, 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, 654659,  DOI: 10.1016/j.jhep.2010.11.021
    28. 28
      Amacher, D. E. (2012) The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin. Drug Metab. Toxicol. 8, 335347,  DOI: 10.1517/17425255.2012.658041
    29. 29
      McGill, M. R. and Jaeschke, H. (2019) Animal models of drug-induced liver injury. Biochim. Biophys. Acta, Mol. Basis Dis. 1865, 10311039,  DOI: 10.1016/j.bbadis.2018.08.037
    30. 30
      Church, 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, 481492,  DOI: 10.1093/toxsci/kfu094
    31. 31
      Stewart, 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, 17911796,  DOI: 10.1002/hep.23891
    32. 32
      Lucena, 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, 303312,  DOI: 10.1002/hep.23668
    33. 33
      Borgne-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 4972, John Wiley & Sons, Hoboken.

    Cited By

    Click to copy section linkSection link copied!

    This article is cited by 2 publications.

    1. Shoumi Haldar, Nounenuo Yhome, Yuvashree Muralidaran, Senthilkumar Rajagopal, Prabhakar Mishra. Nanoplastics Toxicity Specific to Liver in Inducing Metabolic Dysfunction—A Comprehensive Review. Genes 2023, 14 (3) , 590. https://doi.org/10.3390/genes14030590
    2. S. Cyrus Khojasteh, James P. Driscoll, Klarissa D. Jackson, Grover P. Miller, Kaushik Mitra, Ivonne M. C. M Rietjens, Donglu Zhang. Novel advances in biotransformation and bioactivation research—2019 year in review. Drug Metabolism Reviews 2020, 52 (3) , 333-365. https://doi.org/10.1080/03602532.2020.1772281

    Chemical Research in Toxicology

    Cite this: Chem. Res. Toxicol. 2020, 33, 1, 2–4
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.chemrestox.9b00416
    Published December 10, 2019

    Copyright © 2019 American Chemical Society. This publication is available under these Terms of Use.

    Article Views

    1385

    Altmetric

    -

    Citations

    Learn about these metrics

    Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

    Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

    The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

    • This publication has no figures.
    • References


      This article references 33 other publications.

      1. 1
        Labbe, 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, 335353,  DOI: 10.1111/j.1472-8206.2008.00608.x
      2. 2
        Cho, T. and Uetrecht, J. (2017) How reactive metabolites induce an immune response that sometimes leads to an idiosyncratic drug reaction. Chem. Res. Toxicol. 30, 295314,  DOI: 10.1021/acs.chemrestox.6b00357
      3. 3
        Porceddu, 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, 332345,  DOI: 10.1093/toxsci/KFS197
      4. 4
        Ramachandran, 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, 75100,  DOI: 10.18053/jctres.04.201801.005
      5. 5
        Begriche, 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, 773794,  DOI: 10.1016/j.jhep.2010.11.006
      6. 6
        Cho, 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, 14231431,  DOI: 10.1021/acs.chemrestox.9b00116
      7. 7
        Fromenty, B. and Pessayre, D. (1995) Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101154,  DOI: 10.1016/0163-7258(95)00012-6
      8. 8
        McKenzie, 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, 10991105,  DOI: 10.1056/NEJM199510263331702
      9. 9
        Mak, 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, 383392,  DOI: 10.1517/14740338.2016.1139573
      10. 10
        Igoudjil, 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, 273292,  DOI: 10.2174/187152106777697871
      11. 11
        Wang, 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, 11801187,  DOI: 10.1016/j.ajpath.2012.12.033
      12. 12
        Lewis, 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, 7787
      13. 13
        Lebrecht, 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, 7279,  DOI: 10.1002/hep.21490
      14. 14
        Bailey, 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, 26102612,  DOI: 10.1128/AAC.01659-08
      15. 15
        Fromenty, 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, 13771384
      16. 16
        Felser, 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, 480490,  DOI: 10.1093/toxsci/kfs298
      17. 17
        Deschamps, 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, 948961,  DOI: 10.1002/hep.1840190422
      18. 18
        Berson, 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, 261269,  DOI: 10.1016/S0168-8278(00)00050-7
      19. 19
        Wood, 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, R280R284,  DOI: 10.1186/cc3528
      20. 20
        Jiang, 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, 528536,  DOI: 10.1080/15376516.2017.1333553
      21. 21
        Watkins, 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, 5764
      22. 22
        Gokhale, 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, 7071
      23. 23
        Isenberg, 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, 340351,  DOI: 10.1093/toxsci/53.2.340
      24. 24
        Mann, 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, 267278,  DOI: 10.1007/s13577-017-0175-9
      25. 25
        Catta-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, 477485,  DOI: 10.1007/s00428-011-1147-1
      26. 26
        Massart, 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, 147157,  DOI: 10.1007/s40139-013-0022-y
      27. 27
        Tandra, 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, 654659,  DOI: 10.1016/j.jhep.2010.11.021
      28. 28
        Amacher, D. E. (2012) The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury. Expert Opin. Drug Metab. Toxicol. 8, 335347,  DOI: 10.1517/17425255.2012.658041
      29. 29
        McGill, M. R. and Jaeschke, H. (2019) Animal models of drug-induced liver injury. Biochim. Biophys. Acta, Mol. Basis Dis. 1865, 10311039,  DOI: 10.1016/j.bbadis.2018.08.037
      30. 30
        Church, 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, 481492,  DOI: 10.1093/toxsci/kfu094
      31. 31
        Stewart, 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, 17911796,  DOI: 10.1002/hep.23891
      32. 32
        Lucena, 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, 303312,  DOI: 10.1002/hep.23668
      33. 33
        Borgne-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 4972, John Wiley & Sons, Hoboken.