title: CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid.
abstract: Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition-induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002331:Carnitine / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D002784:Cholesterol / Q000097:blood; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D007538:Isoniazid / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D014280:Triglycerides / Q000097:blood
chemical_list: D000995:Antitubercular Agents; D001647:Bile Acids and Salts; D005230:Fatty Acids, Nonesterified; D014280:Triglycerides; D002784:Cholesterol; D019392:Cytochrome P-450 CYP2E1; D002331:Carnitine; D007538:Isoniazid