title: Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis.
abstract: Most cases with antituberculosis drug-induced hepatitis have been attributed to isoniazid. Isoniazid is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. However, the role of CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the CYP2E1 gene is associated with antituberculosis drug-induced hepatitis. A total of 318 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have drug-induced hepatotoxicity. Patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 (CYP2E1 c1/c2 or c2/c2, 9.0%, P =.009). If CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P =.017). Furthermore, under the administration of isoniazid, the volunteers with CYP2E1 c1/c1 genotype had higher CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis.
authors.affiliation: Division of Gastroenterology, Department of Medicine, and the Chest Department, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan. yshuang@vghtpe.gov.tw
authors.forename: Yi-Shin
authors.initials: YS
authors.lastname: Huang
authors.forename: Herng-Der
authors.initials: HD
authors.lastname: Chern
authors.forename: Wei-Juin
authors.initials: WJ
authors.lastname: Su
authors.forename: Jaw-Ching
authors.initials: JC
authors.lastname: Wu
authors.forename: Shi-Chuan
authors.initials: SC
authors.lastname: Chang
authors.forename: Chi-Huei
authors.initials: CH
authors.lastname: Chiang
authors.forename: Full-Young
authors.initials: FY
authors.lastname: Chang
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D013997:Time Factors
chemical_list: D000995:Antitubercular Agents; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D019392:Cytochrome P-450 CYP2E1; D007538:Isoniazid