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

Toxicol Appl Pharmacol. 2013 Jan 15;266(2):245-53. doi: 10.1016/j.taap.2012.10.024. Epub 2012 Nov 8.


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.

MeSH terms

  • Animals
  • Antitubercular Agents / toxicity*
  • Bile Acids and Salts / metabolism*
  • Biological Transport / drug effects
  • Carnitine / metabolism
  • Chemical and Drug Induced Liver Injury / etiology
  • Cholesterol / blood
  • Cytochrome P-450 CYP2E1 / metabolism*
  • Fatty Acids, Nonesterified / metabolism
  • Isoniazid / toxicity*
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Metabolomics
  • Mice
  • Mice, Knockout
  • Triglycerides / blood


  • Antitubercular Agents
  • Bile Acids and Salts
  • Fatty Acids, Nonesterified
  • Triglycerides
  • Cholesterol
  • Cytochrome P-450 CYP2E1
  • Carnitine
  • Isoniazid