抗结核药物性肝损害与CYP2E1和GSTM1基因多态性的相关性研究
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摘要
目的:分析抗结核药物性肝损害(ADIH)与细胞色素P450酶(CYP)2E1和谷胱甘肽-S-转移酶(GST)M1基因多态性的相关性,并探讨其易感因素。方法:选择我院2011年10月-2015年6月收治的我国南方汉族肺结核住院患者91例,根据治疗过程中是否出现ADIH将其分为ADIH组(34例)和无ADIH组(57例);抽取患者外周静脉血,分别采用聚合酶链式反应(PCR)和多重PCR法检测其CYP2E1和GSTM1基因多态性,采用Logistic回归分析考察ADIH的易感因素。结果:所有患者CYP2E1基因型均为c2/c2型(100%);GSTM1基因型分布符合Hardy-Weinberg平衡(P>0.05)。ADIH组GSTM1(+/-)基因型患者有9例(26.5%),GSTM1(-/-)基因型患者有25例(73.5%),差异有统计学意义(P<0.05);无ADIH组GSTM1(+/-)基因型患者有17例(29.8%),GSTM1(-/-)基因型患者有40例(70.2%),差异有统计学意义(P<0.05);但GSTM1(+/-)和(-/-)基因型在两组患者中的分布差异均无统计学意义(P>0.05)。Logistic回归分析结果显示,患者性别、年龄、体质量指数和GSTM1基因型与ADIH均无相关性(P>0.05)。结论:患者性别、年龄、体质量指数和GSTM1基因型可能与ADIH无关。由于仅检出1种CYP2E1基因型,尚无法判断其多态性与ADIH的相关性。
OBJECTIVE:To analyze the association of antituberculosis drug-induced hepatotoxicity(ADIH)with gene polymorphisms of cyptochrome P450(CYP)2E1 and glutathione-S-transferase(GST)M1,and to discuss susceptibility factor. METHODS:91southern and Han inpatients with tuberculosis were selected from our hospital during Oct. 2011-Jun. 2015. According to the occurrence of ADIH,those patients were divided into ADIH group(34 cases)and non-ADIH group(57 cases). Peripheral venous blood of patients were collected,PCR and multiple PCR were used to detect CYP2E1 and GSTM1 gene polymorphisms. The susceptibility factors of ADIH was investigated by Logistic regression analysis. RESULTS:CYP2E1 genotype of all patients were c2/c2 genotype(100%),and GSTM1 genotype distribution met Hardy-Weinberg balance(P>0.05). There were 9 patients(26.5%)with GSTM1(+/-)genotype and 25 patients(73.5%)with GSTM1(-/-)genotype in ADIH group,with statistical significance(P<0.05). There were 17patients(29.8%)with GSTM1(+/-)genotype and 40 patients(70.2%)with GSTM1(-/-)genotype in non-ADIH group,with statistical significance(P<0.05). There was no statistical significance in the distribution of GSTM1(+/-)and(-/-)genotype between 2groups(P>0.05). Logistic regression analysis showed that there was no correlation of gender,age,BMI and GSTM1 genotype with ADIH(P>0.05). CONCLUSIONS:Gender,age,BMI and GSTM1 genotype may be not correlated with ADIH;The relationship of GSTM1 genotype with ADIH can not be judged because only one kind of CYP2E1 genotype has been detected.
OBJECTIVE:To analyze the association of antituberculosis drug-induced hepatotoxicity(ADIH)with gene polymorphisms of cyptochrome P450(CYP)2E1 and glutathione-S-transferase(GST)M1,and to discuss susceptibility factor. METHODS:91southern and Han inpatients with tuberculosis were selected from our hospital during Oct. 2011-Jun. 2015. According to the occurrence of ADIH,those patients were divided into ADIH group(34 cases)and non-ADIH group(57 cases). Peripheral venous blood of patients were collected,PCR and multiple PCR were used to detect CYP2E1 and GSTM1 gene polymorphisms. The susceptibility factors of ADIH was investigated by Logistic regression analysis. RESULTS:CYP2E1 genotype of all patients were c2/c2 genotype(100%),and GSTM1 genotype distribution met Hardy-Weinberg balance(P>0.05). There were 9 patients(26.5%)with GSTM1(+/-)genotype and 25 patients(73.5%)with GSTM1(-/-)genotype in ADIH group,with statistical significance(P<0.05). There were 17patients(29.8%)with GSTM1(+/-)genotype and 40 patients(70.2%)with GSTM1(-/-)genotype in non-ADIH group,with statistical significance(P<0.05). There was no statistical significance in the distribution of GSTM1(+/-)and(-/-)genotype between 2groups(P>0.05). Logistic regression analysis showed that there was no correlation of gender,age,BMI and GSTM1 genotype with ADIH(P>0.05). CONCLUSIONS:Gender,age,BMI and GSTM1 genotype may be not correlated with ADIH;The relationship of GSTM1 genotype with ADIH can not be judged because only one kind of CYP2E1 genotype has been detected.
引文
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[2]全国第五次结核病流行病学抽样调查技术指导组,全国第五次结核病流行病学抽样调查办公室.2010年全国第五次结核病流行病学抽样调查报告[J].中国防痨杂志,2012,34(8):485-508.
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[5]张晓庆,郝晓晖,张利斌,等.CYP2C19基因多态性与抗结核药物性肝损害的关系研究[J].中国药房,2014,25(10):887-890.
[6]周利婷,周燕,张国强,等.异烟肼对小鼠肝细胞膜转运体Mrp2,Bsep,P-gp和Ntcp表达的影响[J].中国药学杂志,2014,49(4):298-302.
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[9]王涛,王巍,王仲元,等.细胞色素P4502E1基因多态性与抗结核药物性肝损害的相关性[J].中华结核和呼吸杂志,2009,32(8):585-587.
[10]王健,刘焯霖,黎锦如,等.中国广东籍汉族人细胞色素P4502El基因5′侧翼区基因多态性[J].中山医科大学学报,1999,20(1):29-31.
[11]冷曙光,宋文佳,王雅文,等.中国汉族人口三种谷胱甘肽S-转移酶基因多态性分析[J].中华预防医学杂志,2001,35(3):159-162.
[12]安慧茹,吴雪琼,王仲元.N-乙酰基转移酶2及谷胱甘肽S转移酶M1基因多态性与抗结核药物性肝损伤的关系研究[J].中国防痨杂志,2014,36(1):14-20.
[13]朱冬林,席云,吴雪琼.GSTM1和GSTT1基因多态性与抗结核药物性肝损害的关系[J].中国抗生素杂志,2011,36(11):864-868.
[14]许瑞,刘亚敏,郭振勇.基因多态性与抗结核药物致肝损害易感性研究进展[J].北京医学,2012,34(9):846-849.
[15]沈婷婷,张琴,张文宏,等.中国汉族结核病患者N-乙酰基转移酶2基因型与药物性肝损伤以及抗结核疗效的关系[J].中华传染病杂志,2015,3(6):327-329.
[2]全国第五次结核病流行病学抽样调查技术指导组,全国第五次结核病流行病学抽样调查办公室.2010年全国第五次结核病流行病学抽样调查报告[J].中国防痨杂志,2012,34(8):485-508.
[3]夏愔愔,詹思延.国内抗结核药品不良反应发生率的综合分析[J].中华结核和呼吸杂志,2007,30(6):419-423.
[4]Tostmann A,Boeree MJ,Aarnoutse RE,et al.Antituberculosis drug-induced hepatotoxicity:concise up-to-date review[J].J Gastroenterol Hepatol,2008,23(2):192-202.
[5]张晓庆,郝晓晖,张利斌,等.CYP2C19基因多态性与抗结核药物性肝损害的关系研究[J].中国药房,2014,25(10):887-890.
[6]周利婷,周燕,张国强,等.异烟肼对小鼠肝细胞膜转运体Mrp2,Bsep,P-gp和Ntcp表达的影响[J].中国药学杂志,2014,49(4):298-302.
[7]叶任高.内科学[M].6版.北京:人民卫生出版社,2014:39-57.
[8]权启镇,孙自勤,王要军.新肝脏病学[M].3版.济南:山东科技出版社,2002:895-899.
[9]王涛,王巍,王仲元,等.细胞色素P4502E1基因多态性与抗结核药物性肝损害的相关性[J].中华结核和呼吸杂志,2009,32(8):585-587.
[10]王健,刘焯霖,黎锦如,等.中国广东籍汉族人细胞色素P4502El基因5′侧翼区基因多态性[J].中山医科大学学报,1999,20(1):29-31.
[11]冷曙光,宋文佳,王雅文,等.中国汉族人口三种谷胱甘肽S-转移酶基因多态性分析[J].中华预防医学杂志,2001,35(3):159-162.
[12]安慧茹,吴雪琼,王仲元.N-乙酰基转移酶2及谷胱甘肽S转移酶M1基因多态性与抗结核药物性肝损伤的关系研究[J].中国防痨杂志,2014,36(1):14-20.
[13]朱冬林,席云,吴雪琼.GSTM1和GSTT1基因多态性与抗结核药物性肝损害的关系[J].中国抗生素杂志,2011,36(11):864-868.
[14]许瑞,刘亚敏,郭振勇.基因多态性与抗结核药物致肝损害易感性研究进展[J].北京医学,2012,34(9):846-849.
[15]沈婷婷,张琴,张文宏,等.中国汉族结核病患者N-乙酰基转移酶2基因型与药物性肝损伤以及抗结核疗效的关系[J].中华传染病杂志,2015,3(6):327-329.