NAT2 and CYP2 E1 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 2 E1 ( CYP2 E1)., 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 ( 282 TT, 590 AA and 857 GA) alleles had an increased susceptibility to anti- TB drug-induced hepatotoxicity. The slow acetylator NAT2 genotypes (especially NAT2*6 A/7 B and NAT2*6 A/6 A) were risk factors for hepatotoxicity (odds ratio ( OR) 9.57 ( P < 0.001) for NAT2*6 A/7 B; OR 5.24 ( P = 0.02) for NAT2*6 A/6 A)., 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*6 A/7 B and NAT2*6 A/6 A 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 CYP2 E1, a metabolic process known to produce hepatotoxic intermediates. [ABSTRACT FROM AUTHOR]