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 P450 2E1 (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.