Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis
Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis
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DOI：
10.1016/j.tube.2007.05.012
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发表时间：
2007-11-01
期刊：
影响因子：
3.2
通讯作者：
Lee, Soo-Youn
中科院分区：
文献类型：
--
作者：
Cho, Hyun-Jung;Koh, Won-Jung;Lee, Soo-Youn
异烟肼（INH）引起的抗结核药物性肝炎是最常见的药物性肝损伤之一。INH通过肝N-乙酰转移酶（NAT）和细胞色素P450 2 E1（CYP 2 E1）代谢形成肝毒素。本研究的目的是评估韩国患者的NAT 2和/或CYP 2 E1基因多态性是否与抗结核药物诱导的肝毒性相关。对132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（PCR）结合或不结合测序测定其NAT 2和CYP 2 E1基因型。18例（13.6%）患者发生抗结核药物性肝毒性。关于NAT 2，慢乙酰化者的肝毒性发生率高于快乙酰化者（36.8% vs. 9.7%，P = 0.005），慢乙酰化者的肝毒性风险是快乙酰化者的3.8倍。对于CYP 2 E1基因，分析了5'非翻译区的Rsal多态性和CYP 2 E1 5'-剥落区的多态性重复序列;任何CYP 2 E1基因型与抗结核药物诱导的肝毒性之间均无显著相关性。总之，NAT 2的慢乙酰化状态是抗结核药物诱导的肝毒性的重要易感风险因素; NAT 2基因分型可能是一个有用的工具。用于预测抗结核药物引起的肝毒性。(c)2007年由Elsevier Ltd.出版
Antituberculosis drug-induced hepatitis attributed to isoniazid (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase (NAT) and cytochrorne P450 2E1 (CYP2E1) to form hepatotoxins. The aim of this study was to evaluate whether polymorphisms of the NAT2 and/or CYP2E1 genes were associated with antituberculosis drug-induced hepatotoxicity in Korean patients. A total of 132 patients with tuberculosis who received antituberculosis treatment were followed prospectively. Their NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction (PCR) with or without sequencing. Eighteen (13.6%) patients developed antituberculosis drug-induced hepatotoxicity. Regarding NAT2, slow acetylators had a higher incidence of hepatotoxicity than rapid acetylators (36.8% vs. 9.7%, P = 0.005) and there was a 3.8-fold risk of hepatotoxicity for the slow acetylators compared to the rapid acetylators. For the CYP2E1 gene, the Rsal potymorphism in the 5' untranslated region, and a polymorphic repetitive sequence at the CYP2E1 5'-flaking region were analyzed; there was no significant association between any CYP2E1 genotype and antituberculosis drug-induced hepatotoxicity. In conclusion, slow acetylator status of NAT2 was a significant susceptibility risk factor for antituberculosis drug-induced hepatotoxicity; NAT2 genotyping may be a useful tool. for predicting antituberculosis drug-induced hepatotoxicity. (c) 2007 Published by Elsevier Ltd.