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Serum Metabolomics Reveals Irreversible Inhibition of Fatty Acid β-Oxidation through the Suppression of PPARα Activation as a Contributing Mechanism of Acetaminophen-Induced Hepatotoxicity

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Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892, and Institute of Pharmacology, First Faculty of Medicine, Charles University, Prague 12800, Czech Republic
* To whom correspondence should be addressed. Tel: 301-402-9067. Fax: 301-496-8419. E-mail: [email protected]
†National Institutes of Health.
‡Current address: Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota 55108.
§Charles University.
Cite this: Chem. Res. Toxicol. 2009, 22, 4, 699–707
Publication Date (Web):March 3, 2009
https://doi.org/10.1021/tx800464q
Copyright © 2009 American Chemical Society

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    Abstract

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    Metabolic bioactivation, glutathione depletion, and covalent binding are the early hallmark events after acetaminophen (APAP) overdose. However, the subsequent metabolic consequences contributing to APAP-induced hepatic necrosis and apoptosis have not been fully elucidated. In this study, serum metabolomes of control and APAP-treated wild-type and Cyp2e1-null mice were examined by liquid chromatography−mass spectrometry (LC-MS) and multivariate data analysis. A dose−response study showed that the accumulation of long-chain acylcarnitines in serum contributes to the separation of wild-type mice undergoing APAP-induced hepatotoxicity from other mouse groups in a multivariate model. This observation, in conjunction with the increase of triglycerides and free fatty acids in the serum of APAP-treated wild-type mice, suggested that APAP treatment can disrupt fatty acid β-oxidation. A time−course study further indicated that both wild-type and Cyp2e1-null mice had their serum acylcarnitine levels markedly elevated within the early hours of APAP treatment. While remaining high in wild-type mice, serum acylcarnitine levels gradually returned to normal in Cyp2e1-null mice at the end of the 24 h treatment. Distinct from serum aminotransferase activity and hepatic glutathione levels, the pattern of serum acylcarnitine accumulation suggested that acylcarnitines can function as complementary biomarkers for monitoring the APAP-induced hepatotoxicity. An essential role for peroxisome proliferator-activated receptor α (PPARα) in the regulation of serum acylcarnitine levels was established by comparing the metabolomic responses of wild-type and Ppara-null mice to a fasting challenge. The upregulation of PPARα activity following APAP treatment was transient in wild-type mice but was much more prolonged in Cyp2e1-null mice. Overall, serum metabolomics of APAP-induced hepatotoxicity revealed that the CYP2E1-mediated metabolic activation and oxidative stress following APAP treatment can cause irreversible inhibition of fatty acid oxidation, potentially through suppression of PPARα-regulated pathways.

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    Table of real-time PCR primers of mouse PPARα-targeted genes, figure of MS2 fragmentation of acylcarnitines, and figure of PCA of time-dependent metabolomic changes induced by 400 mg/kg APAP treatment. This material is available free of charge via the Internet at http://pubs.acs.org.

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