Expression of cytochrome P4502E1 in human liver: Relationship between genotype and phenotype in Chinese

Polymorphic cytochrome P4502E1 (CYP2E1) plays an important role in the metabolic activation of many carcinogens. We have previously shown that the c1/c1 genotype recognized byRsa I in the 5′-regulatory region of theCYP2E1 may be a susceptibility factor for developing esophageal cancer and lung cancer in Chinese. The present study was to investigate the relationship between theRsa I genotype and the expression of CYP2E1 in human livers. A total of 50 liver specimens were genotyped forCYP2E1 and assayed for CYP2E1 protein contents and functional activity by using specific antibody in immunoblot and a probe substrate,p-nitrophenol. A considerable interindividual variation in CYP2E1 protein (20-fold) and functional activity (56-fold) was observed among these liver samples. However, when they were categorized according to genotype, the mean content of CYP2E1 protein was significantly higher among individuals with the c1/c1 genotype than that among those having c1/c2 or c2/c2 genotype [124.0±83.9 pmol/mg (n = 28) versus 65.5 ±38.9 pmol/mg (n = 22),P<0.01]. The mean activity of CYP2E1 towardsp-nitrophenol for the c1/c1 genotype was also higher than that for the variant genotypes (198.4±27.8 pmol/min/mg versus 101.2 ±18.1 pmol^-1 · min^-1 · mg^-1,P<0.01). Also, the protein levels and functional activity showed a significant correlation (r = 0.68,P<0.01). These results demonstrate an association between theRsa I genotype and the phenotype of CYP2E1 in our samples, and the data are compatible with the assumption thatCYP2E1 c1/c1 genotype is a susceptibility factor for certain cancers in Chinese.     

基于全基因组关联的中国常见肿瘤遗传病因学研究

肿瘤是基因-环境交互作用引起的复杂性疾病.在同样的环境暴露下,不同遗传背景的个体发生肿瘤的风险有很大差异.研究肿瘤相关遗传因素对理解肿瘤发生发展乃至诊断治疗都有重要意义.近年来发展的全基因组关联研究(genome-wide association study,GWAS)可在全基因组范围内发现与复杂疾病或表型关联的遗传因素,为复杂疾病遗传学研究提供了强有力的手段.欧美研究者运用全基因组关联研究的方法,对各种常见肿瘤进行了研究,获得了重要成果.2010年以来,中国科学家在国际核心期刊发表了一系列高水平的肿瘤全基因组关联研究成果,在中国常见肿瘤的遗传病因学研究方面取得了重要进展.     

Expression of cytochrome P4502E1 in human liver: Relationship between genotype and phenotype in Chinese

Polymorphic cytochrome P4502E1 (CYP2E1) plays an important role in the metabolic activation of many carcinogens. We have previously shown that the c1/c1 genotype recognized by Rsa I in the 5'-regulatory region of the CYP2E1 may be a susceptibility factor for developing eso-phageal cancer and lung cancer in Chinese. The present study was to investigate the relationship between the Rsa I genotype and the expression of CYP2E1 in human livers. A total of 50 liver specimens were genotyped for CYP2E1 and assayed for CYP2E1 protein contents and functional activity by using specific antibody in immunoblot and a probe substrate, p-nitrophenol. A considerable interindividual variation in CYP2E1 protein (20-fold) and functional activity (56-fold) was observed among these liver samples. However, when they were categorized according to genotype, the mean content of CYP2E1 protein was significantly higher among individuals with the c1/c1 genotype than that among those having c1/c2 or c2/c2 genotype [124.0 ±83.9 pmol/     

中国人肝脏细胞色素P450 2E1表达——基因型与表型的关系

细胞色素P450(CYP)2E1代谢激活多种致癌物并参与酒精代谢和自由基形成,其基因启动子区RsaⅠ单核苷酸多态与酒精性肝病和某些癌症如食管癌和肺癌的易感性相关.以免疫印迹和特异底物的方法研究了RsaⅠ识别的不同基因型肝脏标本中CYP2E1蛋白含量及其功能活性的差异.结果表明,c1/c1基因型(n=28)的蛋白含量((124.0±83.9)pmol/mg)高于携带至少一个c2等位基因的变异基因型((65.5 ± 38.9)pmol/mg,n=22),差异有极显著性(P<0.01).c1/c1基因型的肝微粒体代谢4-硝基苯酚的活性也同样显著高于变异基因型((198.4 ± 27.8)pmol/(min· mg)比 (101.2 ± 18.1)pmol/(min·mg),P <0.01)).结果证明,CYP2E1表达水平和酶活性的个体差异与RsaⅠ识别的基因多态有关,这与分子流行病学研究发现的c1/c1基因型是某些癌症的遗传易感因素一致.