Ben Fredj N, Gam R, Kerkni E, Chaabane A, Chadly Z, Boughattas N, Aouam K
Laboratoire de Pharmacologie, Faculté de Médecine de Monastir, Service de Pharmacologie Clinique, Monastir, Tunisia.
UR12ES10, Faculté de Médecine de Monastir, Monastir, Tunisie.
Pharmacogenomics J. 2017 Jul;17(4):372-377. doi: 10.1038/tpj.2016.26. Epub 2016 Apr 19.
Previous studies have shown controversial results on whether acetylator status causes isoniazid-induced hepatotoxicity (IIH). Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear. The objectives of this study were (i) to assess the quantitative relationship between the level of isoniazid serum concentration and the incidence of IIH and (ii) to evaluate the extent of implication of the N-acetyltransferase-2 (NAT2) and CYP2E1 polymorphisms genes to induce this disorder. Seventy-one patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction. Three restriction enzymes, RsaI, PstI and DraI were used to detect CYP2E1 RFLP and four different restriction enzymes, KpnI, TaqI, BamHI and Ddel were used to determine NAT2 acetylator status. Therapeutic drug monitoring (TDM) of isoniazid (serum concentration performed 3 h after the morning dose: C3) was performed. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Receiver Operating Characteristics curve analysis was used to evaluate the relationship between risk factors and the incidence of IIH. Eleven (15.4%) patients have developed IIH. Demographic factors, including age, weight and gender were not associated with the incidence of hepatotoxicity. High serum concentration of isoniazid (C3) was found to be a risk factor of IIH (area under the curve: 0.74, P=0.007, 95% confidence interval (95% CI): 0.56-0.93), with a cutoff value at 3.69 mg l (odds ratio (OR): 13.2, P=0.0007, 95% CI: 2.9-59). Multivariate analysis showed that only a C3 over 3.69 mg l remains a risk factor of IIH. NAT2 and CYP2E1 variants were not found to increase the risk of IIH when analyzed separately. However, combined analysis of the NAT2/CYP2E1 gene polymorphisms showed that patients with both DraI C/D and slow acetylator have an increased risk of IIH compared with other combined NAT2/CYP2E1 genotype profiles (OR: 8.41, P=0.01, 95% CI: 1.54-45.76). Our results suggest that a serum concentration of isoniazid over 3.69 mg l and a combined genotype CYP2E1 DraI(C/D)/slow acetylator are major risk factors for IIH. Therefore, TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.
先前的研究在乙酰化状态是否会导致异烟肼诱发的肝毒性（IIH）方面呈现出有争议的结果。此外，参与肝毒素形成的肝脏酶细胞色素P450 2E1（CYP2E1）对发生IIH风险的影响仍不明确。本研究的目的是：（i）评估异烟肼血清浓度水平与IIH发生率之间的定量关系；（ii）评估N - 乙酰转移酶2（NAT2）和CYP2E1基因多态性对诱发这种疾病的影响程度。纳入了71例接受常规抗结核治疗方案的结核病患者。使用聚合酶链反应确定NAT2和CYP2E1基因型。使用三种限制性内切酶RsaI、PstI和DraI检测CYP2E1限制性片段长度多态性（RFLP），并使用四种不同的限制性内切酶KpnI、TaqI、BamHI和Ddel确定NAT2乙酰化状态。对异烟肼进行治疗药物监测（TDM）（早晨给药3小时后测定血清浓度：C3）。根据贝尼舒等人的标准诊断异烟肼诱发的肝毒性病例。采用受试者工作特征曲线分析来评估危险因素与IIH发生率之间的关系。11例（15.4%）患者发生了IIH。人口统计学因素，包括年龄、体重和性别，与肝毒性发生率无关。发现异烟肼高血清浓度（C3）是IIH的一个危险因素（曲线下面积：0.74，P = 0.007，95%置信区间（95%CI）：0.56 - 0.93），临界值为3.69 mg/l（比值比（OR）：13.2，P = 0.0007，95%CI：2.9 - 59）。多变量分析表明，只有C3超过3.69 mg/l仍然是IIH的一个危险因素。单独分析时，未发现NAT2和CYP2E1变异会增加IIH风险。然而，对NAT2/CYP2E1基因多态性的联合分析表明，与其他联合的NAT2/CYP2E1基因型谱相比，同时具有DraI C/D和慢乙酰化型的患者发生IIH的风险增加（OR：8.41，P = 0.01，95%CI：1.54 - 45.76）。我们的结果表明，异烟肼血清浓度超过3.69 mg/l以及联合基因型CYP2E1 DraI（C/D）/慢乙酰化型是IIH的主要危险因素。因此，异烟肼的TDM以及NAT2和CYP2E1基因型的测定可能有助于预测和预防突尼斯结核病患者的IIH。
