Document Detail


CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid.
MedLine Citation:
PMID:  23142471     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Jie Cheng; Kristopher W Krausz; Feng Li; Xiaochao Ma; Frank J Gonzalez
Publication Detail:
Type:  Journal Article     Date:  2012-11-08
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  266     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-01     Completed Date:  2013-02-19     Revised Date:  2014-01-23    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  245-53     Citation Subset:  IM    
Copyright Information:
Published by Elsevier Inc.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Antitubercular Agents / toxicity*
Bile Acids and Salts / metabolism*
Biological Transport / drug effects
Carnitine / metabolism
Cholesterol / blood
Cytochrome P-450 CYP2E1 / metabolism*
Drug-Induced Liver Injury / etiology
Fatty Acids, Nonesterified / metabolism
Isoniazid / toxicity*
Liver / drug effects*,  metabolism
Male
Metabolomics
Mice
Mice, Knockout
Triglycerides / blood
Grant Support
ID/Acronym/Agency:
Z01 BC005562-21/BC/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antitubercular Agents; 0/Bile Acids and Salts; 0/Fatty Acids, Nonesterified; 0/Triglycerides; 541-15-1/Carnitine; 97C5T2UQ7J/Cholesterol; EC 1.14.14.1/Cytochrome P-450 CYP2E1; V83O1VOZ8L/Isoniazid
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Zinc oxide nanoparticles and monocytes: Impact of size, charge and solubility on activation status.
Next Document:  Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and...