NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients

Clin Exp Pharmacol Physiol. 2012 Jun;39(6):535-43. doi: 10.1111/j.1440-1681.2012.05713.x.

Abstract

1. The present study investigated the relationship between antituberculosis (anti-TB) drug-induced hepatotoxicity and genetic polymorphisms of two important drug-metabolizing enzymes involved in the metabolism of isoniazid, namely N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). 2. A polymerase chain reaction direct sequencing approach was used to detect genetic polymorphisms of the NAT2 and CYP2E1 genes in tuberculosis (TB) patients with (n = 101) or without (n = 107) anti-TB drug-induced hepatotoxicity. Associations between various genetic polymorphisms and anti-TB drug-induced hepatotoxicity were then determined. 3. Patients with NAT2 (282TT , 590AA and 857GA) alleles had an increased susceptibility to anti-TB drug-induced hepatotoxicity. The slow acetylator NAT2 genotypes (especially NAT2*6A/7B and NAT2*6A/6A) were risk factors for hepatotoxicity (odds ratio (OR) 9.57 (P < 0.001) for NAT2*6A/7B; OR 5.24 (P = 0.02) for NAT2*6A/6A). 4. The CYP2E1 genotype per se was not significantly associated with the development of anti-TB drug-induced hepatotoxicity. However, the combination of the CYP2E1 C1/C1 genotype with a slow acetylator NAT2 genotype increased the risk of anti-TB drug-induced hepatotoxicity (OR 5.33; P = 0.003) compared with the combination of a rapid acetylator NAT2 genotype with either a C1/C2 or C2/C2 genotype. 5. Thus, slow acetylators with the NAT2*6A/7B and NAT2*6A/6A genotypes combined with the C1/C1 CYP2E1 genotype may be involved in the pathogenesis of anti-TB drug-induced hepatotoxicity. 6. The present findings may be explained, in part, by changes in the metabolism of the anti-TB drug isoniazid induced via NAT2 and CYP2E1, a metabolic process known to produce hepatotoxic intermediates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antitubercular Agents / adverse effects*
  • Arylamine N-Acetyltransferase / genetics*
  • Asian Continental Ancestry Group / genetics*
  • Chemical and Drug Induced Liver Injury / epidemiology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Cytochrome P-450 CYP2E1 / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic / genetics*
  • Risk Factors
  • Young Adult

Substances

  • Antitubercular Agents
  • Cytochrome P-450 CYP2E1
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human