Ethnic/Racial Differences in 1, 3-Bitadiene Metabolism and DNA Adduct Formation

丁二烯是一种重要的烟草烟雾致癌物质，可能与肺癌的诱发有关 在吸烟者身上。根据流行病学证据，丁二烯被归类为已知的人类致癌物质 表明职业暴露工人的癌症发病率增加，在#年的吸入研究中 实验动物。公认的丁二烯致癌的关键步骤是化学物质 丁二烯的环氧代谢物修饰DNA形成共价加合物。之前的研究已经 新陈代谢和修复基因的遗传变异可以调节对丁二烯的敏感性 突变和癌症。由于需要丁二烯的代谢激活，所以酶 参与丁二烯环氧化物的形成和解毒的物质在很大程度上决定了个体 对丁二烯介导的突变和致癌的敏感性。中的许多显著的多态 编码丁二烯代谢酶的基因，如CYP2E1、EPHX1。和GSTT1，已被鉴定。 由于它们的频率在不同的民族/种族群体中不同，这些基因变化可能导致 观察到不同种族/种族之间肺癌发病率的差异。未来的研究是有必要的 确定生物转化基因的表达水平和遗传变异如何影响 丁二烯在人体内的代谢和生物学效应。 我们假设不同种族/种族的人类群体代谢丁二烯的差异， 暴露于烟草烟雾中的丁二烯会导致不同程度的癌症风险。这一应用的目的是研究丁二烯代谢和丁二烯诱导的DNA加合物形成的个体间和种族间的差异，并将这些差异与致癌物代谢和DNA修复基因的特定多态性联系起来。本文提出的研究将量化不同种族吸烟者中丁二烯和丁二烯诱导的DNA加合物的主要尿代谢物，并确定基因多态对丁二烯衍生环氧化物遗传毒性的影响。我们的方法是创新的，因为我们将第一次分析种族/种族对丁二烯代谢和DNA加合物形成的影响，在一个大型的多民族队列中。

Butadiene is an important tobacco smoke carcinogen likely to be involved in the induction of lung tumors in smokers. Butadiene is classified as a known human carcinogen based on epidemiological evidence indicating increased cancer incidence in occupationally exposed workers and in inhalation studies in laboratory animals. The recognized critical step in butadiene-mediated carcinogenesis is the chemical modification of DNA by the epoxy metabolites of butadiene to form covalent adducts. Previous studies have shown that genetic variations in metabolism and repair genes can mediate the sensitivity to butadieneinduced mutations and cancer. Because ofthe requirement for metabolic activation of butadiene, enzymes that are involved in the formation and detoxification of butadiene epoxides largely determine the individual sensitivity to butadiene-mediated mutagenesis and carcinogenesis. Many prominent polymorphisms in genes coding for butadiene metabolizing enzymes, e.g. CYP2E1, EPHX1. and GSTT1, have been identified. Because their frequency differs between ethnic/racial groups, these genetic changes may contribute to the observed inter-ethnic/inter-racial differences in the incidence of lung cancer. Future studies are warranted to determine how the expression levels and genetic variations in biotransformation genes influence the metabolism and biological effects of butadiene in humans. We hypothesize that human populations of different ethnicity/race metabolize butadiene differentiy, contributing to differing degrees of cancer risk following exposure to butadiene in tobacco smoke. The obiective of this application is to investigate inter-individual and inter-ethnic/racial differences in the metabolism of butadiene and in the formation of butadiene-induced DNA adducts and to link these differences to specific polymorphisms of carcinogen metabolism and DNA repair genes. Studies proposed here will quantify the major urinary metabolites of butadiene and butadiene-induced DNA adducts in smokers of varying ethnic groups and identify the effects of genetic polymorphisms on the genotoxicity of butadienederived epoxides. Our approach is innovative, because we will, for the flrst time, analyze the effects of ethnicity/race on butadiene metabolism and DNA adduct formation in a large multi-ethnic cohort.