Cytochrome p450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis
Cytochrome p450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis
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DOI：
10.1053/jhep.2003.50144
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发表时间：
2003-04-01
期刊：
影响因子：
13.5
通讯作者：
Lee, SD
中科院分区：
文献类型：
--
作者：
Huang, YS;Chern, HD;Lee, SD
大多数抗结核药物引起的肝炎病例归因于异烟肼。异烟肼经肝脏N-乙酰转移酶（NAT）和细胞色素P450 2E1（CYP2E1）代谢形成肝毒素。然而，CYP2E1在这种肝毒性中的作用尚未报道。本研究旨在探讨CYP2E1基因多态性与抗结核药物性肝炎的关系。对318例接受抗结核治疗的肺结核患者进行前瞻性随访。采用聚合酶链反应-限制性片段长度多态性方法测定CYP2E1和NAT2基因型。招募21名健康志愿者，采用氯唑沙宗试验进行CYP2E1表型研究。49例（15.4%）患者被诊断为药物诱导的肝毒性。携带纯合子野生型CYP2E1 c1/c1的患者发生肝毒性的风险（20.0%;比值比[OR]，2.52）高于携带突变型等位基因c2的患者（CYP2E1 c1/c2或c2/c2，9.0%，P =.009）。以CYP2E1 c1/c2或c2/c2基因型合并快速乙酰化状态为参照组，肝毒性风险由快速乙酰化状态CYP2E1 c1/c1的3.94增加到缓慢乙酰化状态CYP2E1 c1/c1的7.43。调整乙酰化状态和年龄后，CYP2E1 c1/c1基因型仍然是肝毒性的独立危险因素（OR，2.38; P =.017）。此外，在服用异烟肼时，CYP2E1 c1/c1基因型的志愿者比其他基因型的志愿者具有更高的CYP2E1活性，因此可能产生更多的肝毒素。总之，CYP 2E1基因多态性可能与抗结核药物性肝炎的易感性相关。
Most cases with antituberculosis drug-induced hepatitis have been attributed to isoniazid. Isoniazid is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. However, the role of CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the CYP2E1 gene is associated with antituberculosis drug induced hepatitis. A total of 318 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have drug-induced hcpatotoxicity. Patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 (CYP2E1 c1/c2 or c2/c2, 9.0%, P = .009). If CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P = .017). Furthermore, under the administration of isoniazid, the volunteers with CYP2E1 c1/c1 genotype had higher CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis.