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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 ?-oxidation.

SUBMITTER: Cheng J

PROVIDER: S-EPMC3661416 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid.

Cheng Jie J Krausz Kristopher W KW Li Feng F Ma Xiaochao X Gonzalez Frank J FJ

Toxicology and applied pharmacology 20121108 2

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 toxi ...[more]

PMID: 23142471

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CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid.

Publications

CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid.

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