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

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 P4502E1 (CYP2E1). 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. 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 ). 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. 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. 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.