The effect of genetic polymorphisms in the vinyl chloride metabolic pathway on mutagenic risk
The effect of genetic polymorphisms in the vinyl chloride metabolic pathway on mutagenic risk
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DOI：
10.1007/s10038-007-0134-5
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发表时间：
2007-03
影响因子：
3.5
通讯作者：
Jennifer Schindler;Yong-liang Li;M. Marion;Arianne Paroly;P. Brandt-rauf
中科院分区：
文献类型：
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作者：
Jennifer Schindler;Yong-liang Li;M. Marion;Arianne Paroly;P. Brandt-rauf
氯乙烯（VC）是一种人类致癌物，已知可通过细胞色素P450 2 E1（CYP 2 E1）代谢为可引起致癌基因和肿瘤抑制基因突变的反应性中间体，并进一步通过乙醛脱氢酶（ALDH 2）和谷胱甘肽-S-转移酶（GST）代谢为非致突变性终产物。这些代谢酶具有已知的多态性，可能导致VC活性中间体水平增加，从而增加暴露后突变和癌症的风险。使用限制性片段长度多态性（RFLP）分析，我们研究了一个队列的597名法国VC工人的多态性在CYP 2 E1，ALDH 2，GSTM 1和GSTT 1的突变癌基因和肿瘤抑制基因的生物标志物，可归因于VC暴露的发生。发现突变ras-p21和突变p53的生物标志物的存在与累积VC暴露高度显著相关（趋势P < 0.0001）。发现CYP 2 E1变异体c2等位基因的存在与一种或两种突变生物标志物的存在显著相关，即使在控制了包括累积VC暴露在内的潜在混杂因素后也是如此（OR= 2.3，95% CI= 1.2-4.1），并且c2等位基因和VC暴露的影响近似相加。在控制混杂因素后，发现GSTT 1无效状态与一种或两种生物标志物的存在增加，但无显著相关性（OR= 1.3，95%CI = 0.8-2.0）。这些结果表明，在VC代谢途径和VC暴露的多态性，可能有助于可变的易感性暴露人群中的VC的诱变效应之间存在一种可能的基因-环境相互作用。
Vinyl chloride (VC) is a human carcinogen known to undergo metabolism by cytochrome P450 2E1 (CYP2E1) to reactive intermediates that can cause oncogene and tumor suppressor gene mutations and that are further metabolized by acetaldehyde dehydrogenase (ALDH2) and glutathione-S-transferases (GSTs) to non-mutagenic end products. These metabolic enzymes have known polymorphisms that could lead to increased levels of the VC reactive intermediates and thus an increased risk for mutations and cancer following exposure. Using restriction fragment length polymorphism (RFLP) analysis, we have examined a cohort of 597 French VC workers for polymorphisms in CYP2E1, ALDH2, GSTM1 and GSTT1 in relation to the occurrence of mutant oncogene and tumor suppressor gene biomarkers that are attributable to VC exposure. The presence of the biomarkers for mutant ras-p21 and mutant p53 was found to be highly significantly associated with cumulative VC exposure (P for trend< 0.0001). The presence of the CYP2E1 variant c2 allele was found to be significantly associated with the presence of either or both mutant biomarkers even after controlling for potential confounders including cumulative VC exposure (OR= 2.3, 95% CI= 1.2–4.1), and the effects of the c2 allele and VC exposure were approximately additive. GSTT1 null status was found to have an increased, but not significant association with the presence of either or both biomarkers after controlling for confounders (OR= 1.3, 95% CI= 0.8–2.0). These results suggest the existence of a possible gene–environment interaction between polymorphisms in the VC metabolic pathway and VC exposure that could contribute to the variable susceptibility to the mutagenic effects of VC in exposed populations.