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NAT 2 and CYP 2 E 1 polymorphisms associated with antituberculosis drug‐induced hepatotoxicity in C hinese patients
Author(s) -
An HuiRu,
Wu XueQiong,
Wang ZhongYuan,
Zhang JunXian,
Liang Yan
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2012.05713.x
Subject(s) - nat , genotype , arylamine n acetyltransferase , cyp2e1 , isoniazid , pharmacology , tuberculosis , drug , allele , medicine , chemistry , cytochrome p450 , biology , gene , genetics , enzyme , biochemistry , pathology , computer network , computer science
Summary 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 ( NAT 2) and cytochrome P 450 2 E 1 ( CYP 2 E 1). 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 NAT 2*6 A /7 B and NAT 2*6 A /6 A ) were risk factors for hepatotoxicity (odds ratio ( OR ) 9.57 ( P < 0.001) for NAT 2*6 A /7 B ; OR 5.24 ( P = 0.02) for NAT 2*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 CYP2E1C 1 / C 1 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 C 1 / C 2 or C 2 / C 2 genotype. Thus, slow acetylators with the NAT 2*6 A /7 B and NAT 2*6 A /6 A genotypes combined with the C 1 / C 1 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 NAT 2 and CYP 2 E 1, a metabolic process known to produce hepatotoxic intermediates.