CYP450、GSTs、UGT基因多态性与抗结核药物肝损伤的关系  

Relationships of CYP450,GSTs,and UGT gene polymorphisms with anti-tuberculosis drug-induced liver injury

作　　者：孙淑丰 李标 崇英之 杜莹 

机构地区：[1]华北理工大学,河北唐山063210

出　　处：《山东医药》2017年第39期6-10,共5页Shandong Medical Journal

基　　金：国家自然科学基金项目(81041096)

摘　　要：目的探讨细胞色素P450(CYP450)、谷胱甘肽转移酶(GSTs)、尿苷二磷酸葡萄糖醛酸转移酶(UGT)基因多态性及其交互作用与抗结核药物性肝损伤(ADLI)发生的关系。方法选择接受抗结核化疗6个月内出现肝损伤的汉族结核病患者207例纳入病例组,以同期治疗中未出现肝功能异常的结核病患者207例为对照组。采用聚合酶链反应-限制性片段长度多态性法观察CYP1A2 734C/A、CYP3A4 18B-20232G/A、CYP3A5 3-6986A/G、CYP2C19 681G/A、GSTA1-69C/T、GSTM3缺失突变、UGT2B7-268A/G、UGT2B7 802C/T位点的多态性。采用单因素、多因素Logistics回归分析法分析CYP450、GSTs、UGT基因多态性与ADLI发生的关系。采用多因子降维法分析CYP450、GSTs、UGT基因多态性位点之间的交互作用与ADLI发生的关系。结果 CYP1A2 734C/A的AA基因型、CYP3A4 18B-20232G/A的GA基因型、UGT2B7-268A/G的AG基因型、UGT2B7 802C/T的TT基因型是ADLI的保护基因型,而CYP3A5 3-6986A/G的AG及GG基因型、GSTA1-69C/T的TT基因型则是ADLI的危险基因型。调整其他基因多态性的影响后,发现CYP3A4*18B-20232G/A、CYP3A5*3-6986A/G、UGT2B7-268A/G和UGT2B7802C/T位点基因多态性与ADLI的发生有关。多因子降维法分析得到UGT2B7-268A/G、CYP3A4 18B-20232G、CYP3A5 3-6986G组成的3因素模型为最佳模型,检验样本准确度为61.29%,交叉验证一致性为10/10。最佳模型的估计结果显示,与低危基因型组合相比,高危基因型组合显著增加ADLI的发病风险。结论 CYP3A4*18B-20232G/A、CYP3A5*3-6986A/G、UGT2B7-268A/G、UGT2B7 802C/T位点基因多态性与ADLI的发生有关,且基因位点之间存在交互作用,其中UGT2B7-268A/G、CYP3A4 18B-20232G、CYP3A5 3-6986G组合将显著增加ADLI的发生风险。Objective To investigate the correlations of drug metabolic enzymes cytochrome P450（ CYP450）,glutathione S-transferases（ GSTs）,and uridine diphosphate glycosyltransferase（ UGT） gene single nucleotide polymorphisms（ SNPs） with anti-tuberculosis drug-induced liver injury（ ADLI）. Methods We selected 207 cases of Han tuberculosis（ TB） patients who experienced liver injury within 6 months of anti-TB chemotherapy treatment as the case group and 207 cases of TB patients with no abnormal liver function as the control group. Polymerase chain reaction restriction fragment length polymorphism（ PCR-RFLP） was employed to identify the SNPs of CYP1 A2 734 C/A,CYP3 A4 18 B-20232 G/A,CYP3 A5 3-6986 A/G,CYP2 C19 681 G/A,GSTA1-69 C/T,and GSTM3 deletion mutation,and UGT2 B7-268 A/G and UGT2 B7 802 C/T. We adopted univariate and multivariate logistic regression methods to discuss the relationships of CYP450,GSTs,and UGT gene SNPs with ADLI. Multifactor dimensionality reduction（ MDR） method was used to explore the interaction between ADLI and SNPs. Results Univariate and multivariate logistic regression analysis showed that the genotype AA of CYP1 A2 734 C/A,the genotype GA of CYP3 A4＊ 18 B-20232 G/A,the genotype AG of UGT2 B7-268 A/G,and the genotype TT of UGT2 B7 802 C/T were the protective genotypes of ADLI,and the mutant genotypes AG and GG of CYP3 A5＊ 3-6986 A/G and the genotype TT of GSTA1-69 C/T were the risk genotypes of ADLI. After adjusting the effects of other gene SNPs,we found that CYP3 A4 ＊ 18 B-20232 G/A,CYP3 A5 ＊ 3-6986 A/G,UGT2 B7-268 A/G,and UGT2 B7802 C/T were related to the occurrence of ADLI. A best model consisted of three factors UGT2 B7-268 A/G,CYP3 A4 18 B-20232 G,and CYP3 A5 3-6986 G,with the sample accuracy of 61. 29% and the cross-validation consistency of 10/10,was obtained by MDR,and the high risk genotype combination could increase risk of ADLI. Conclusions CYP3 A4 ＊ 18 B-20232 G/A,CYP3 A5＊ 3-6986 A/G,UGT2 B7-268 A/G,and UGT2 B7 802 C/T gene SNPs are related to

关 键 词：结核病 抗结核药 药物性肝损伤 药物代谢酶 细胞色素P450 谷胱甘肽转移酶 尿苷二磷酸葡萄糖醛酸转移酶 基因多态性 

分 类 号：R575[医药卫生—消化系统]