Effect of the CYP2E1 genotype on vinyl chloride monomer-induced liver fibrosis among polyvinyl chloride workers
Effect of the CYP2E1 genotype on vinyl chloride monomer-induced liver fibrosis among polyvinyl chloride workers
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DOI：
10.1016/j.tox.2007.06.089
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发表时间：
2007-09-24
期刊：
影响因子：
4.5
通讯作者：
Cheng, Tsun-Jen
中科院分区：
文献类型：
--
作者：
Hsieh, Hui-I;Chen, Pau-Chung;Cheng, Tsun-Jen
尽管氯乙烯单体(VCM)与肝硬变之间的关系已有报道，但其潜在的机制尚不清楚。细胞色素P4502E1、乙醛脱氢酶2和谷胱甘肽S转移酶1参与了血管紧张素转换酶的激活和解毒，可能是包括肝硬变在内的血管紧张素转换酶诱导的肝损伤个体间易感性的重要决定因素。这项研究的目的是评估代谢基因多态是否可以改变暴露于VCM的个体对肝纤维化的易感性。采用聚合酶链式反应-限制性片段长度多态性方法，对5家聚氯乙烯制造厂的320名工人进行了CYP2E1、ALDH2和GSTT1基因多态性的检测。研究对象的累积氯乙烯暴露水平是使用工作暴露矩阵模型计算的。对13名作业工人进行超声检查，诊断为肝纤维化。我们观察到VCM暴露和肝纤维化之间的剂量-反应趋势。在遗传多态研究中，与携带c1c1或c1c2基因的个体相比，携带c2c2基因的个体发生肝纤维化的风险显著增加。GSTT1和ALDH2基因分型与肝纤维化程度无明显差异。综上所述，我们的结果提示，在慢性VCM暴露中，CYP2E1基因多态性可能是导致肝纤维化易感性的个体差异的原因。因此，代谢酶的多态性分析可能有助于VCM接触者肝损伤的风险评估。(C)2007爱思唯尔爱尔兰有限公司。保留所有权利。
Although a relationship between vinyl chloride monomer (VCM) and liver cirrhosis has been reported, the underlying mechanisms are not clear. Cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2) and glutathione S-transferase theta 1 (GSTT1) enzymes are involved in activation and detoxification of VCM, and thus may be important determinants of interindividual susceptibility to VCM-induced liver damage, including liver cirrhosis. The objective of this study was to evaluate if metabolizing genetic polymorphisms could modify individual susceptibility to liver fibrosis of the VCM exposure. CYP2E1, ALDH2, and GSTT1 polymorphisms were determined by the PCR-RFLP method among 320 workers who were employed in five polyvinyl chloride manufacturing plants. Cumulative VCM exposure levels for study subjects were calculated using a job exposure matrix model. Thirteen workers were diagnosed as having liver fibrosis by using ultrasonography. We observed a dose-response trend between VCM exposure and liver fibrosis. Regarding the results on genetic polymorphisms, CYP2E1 c2c2 genotype showed a significant increase in the risk of liver fibrosis as compared to those with CYP2E1 c1c1 or c1c2 genotypes. No differences were observed between GSTT1 and ALDH2 genotypes and liver fibrosis. In summary, our result suggests that genetic polymorphism in CYP2E1 may be responsible for individual differences in susceptibility to liver fibrosis with regard to chronic VCM exposure. Thus, polymorphism analysis of metabolizing enzymes might be useful in the risk assessment of liver damage in workers with VCM exposure. (c) 2007 Elsevier Ireland Ltd. All rights reserved.