Laboratório de Genética Humana, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
Mem Inst Oswaldo Cruz. 2011 Sep;106(6):716-24. doi: 10.1590/s0074-02762011000600011.
Isoniazid (INH), one of the most important drugs used in antituberculosis (anti-TB) treatment, is also the major drug involved in hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, such as NAT2, CYP2E1, GSTM1 and GSTT1, that code for drug-metabolising enzymes. Our goal was to examine the polymorphisms in these enzymes as susceptibility factors to anti-TB drug-induced hepatitis in Brazilian individuals. In a case-control design, 167 unrelated active tuberculosis patients from the University Hospital of the Federal University of Rio de Janeiro, Brazil, were enrolled in this study. Patients with a history of anti-TB drug-induced acute hepatitis (cases with an increase to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis) and patients with no evidence of anti-TB hepatic side effects (controls) were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms. Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators [22% (18/82) vs. 9.8% (6/61), odds ratio (OR), 2.86, 95% confidence interval (CI), 1.06-7.68, p = 0.04). Logistic regression showed that slow acetylation status was the only independent risk factor (OR 3.59, 95% CI, 2.53-4.64, p = 0.02) for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals.
异烟肼（INH）是抗结核（anti-TB）治疗中最重要的药物之一，也是导致肝毒性的主要药物。INH 诱导的毒性差异归因于几个基因座的遗传多态性，如 NAT2、CYP2E1、GSTM1 和 GSTT1，这些基因座编码药物代谢酶。我们的目标是研究这些酶的多态性是否为巴西个体抗结核药物引起肝炎的易感因素。在病例对照设计中，巴西里约热内卢联邦大学附属医院的 167 名无关联活动性肺结核患者纳入本研究。具有抗结核药物引起急性肝炎病史的患者（病例组：血清转氨酶升高至正常值上限的 3 倍，伴有肝炎症状）和无抗结核肝副作用证据的患者（对照组）进行 NAT2、CYP2E1、GSTM1 和 GSTT1 多态性基因分型。慢乙酰化者发生肝炎的发生率高于中间/快速乙酰化者[22%（18/82）与 9.8%（6/61），比值比（OR）2.86，95%置信区间（CI）1.06-7.68，p=0.04]。Logistic 回归显示，慢乙酰化状态是异烟肼方案抗结核治疗中巴西个体发生抗结核药物引起肝炎的唯一独立危险因素（OR 3.59，95%CI 2.53-4.64，p=0.02）。
