Project 3 - Ethnic/racial Differences in Metabolism and DNA Adduct Formation by 1,3-Butadiene

摘要 丁醇是一种重要的烟草烟雾致癌物，可能参与肺肿瘤的诱导 吸烟者。根据流行病学证据，丁氨酰被列为已知的人类致癌物 表明在职业接触工人中癌症发病率增加， 实验室动物在丁二烯介导的致癌作用中公认的关键步骤是化学 丁二烯的环氧化物代谢物对DNA的修饰，形成共价加合物。以前的研究 已经表明，代谢和修复基因的遗传变异可以介导对 丁二烯诱发的突变和癌症。由于需要代谢活化， 丁二烯，主要参与丁二烯环氧化物的形成和解毒的酶 测定个体对丁二烯介导的诱变和致癌作用的敏感性。许多 已经鉴定了编码丁二烯代谢酶的基因的显著多态性。 由于其频率在种族/种族群体之间存在差异，这些遗传变化可能有助于 观察到的肺癌发病率的种族间/种族间差异。在此前的融资中， 期间，我们观察到尿液中丁硫醇排泄量存在显着的种族差异 白色人、非裔美国人、日裔美国人和夏威夷土著人吸烟者的酸。这些结果 表明由于遗传变异，这些种族群体对丁二烯的代谢方式不同 生物转化基因如谷胱甘肽-S-转移酶1（GSTT 1）。 我们现在假设，由于丁二烯代谢的种族差异， 不同的种族/人种形成不同数量的丁二烯-DNA加合物，这有助于种族 暴露于烟草烟雾中的丁二烯后癌症风险的差异。的目的 应用是研究丁二烯形成中的个体间和种族/人种间差异， 在吸烟者中诱导DNA加合物，以确定其在肺癌风险中的作用，并将个体间 丁二烯对致癌物代谢和DNA特异性多态性反应的差异 修复基因我们的方法是创新的，因为我们将首次检查丁二烯-DNA 在一个大型的多种族吸烟者队列中，评价丁二烯与 暴露和肺癌，并评估特定的遗传多态性对丁二烯的影响 在人HapMap细胞培养物中的代谢、DNA加合物形成、毒性和突变。 预期结果：虽然吸烟是公认的肺癌风险因素，但五分之一的人 美国人继续吸烟。大约11- 24%的吸烟者在一生中会患上肺肿瘤， 非裔美国人和夏威夷土著吸烟者的癌症发病率高于 欧洲裔美国人、日裔美国人和拉丁裔美国人。我们的研究将有助于深入了解 吸烟介导的肺癌敏感性的这种变异性的起源，并帮助识别风险个体 他们应该是特殊戒烟干预或化学预防治疗的候选人。

ABSTRACT 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 epoxide metabolites of butadiene to form covalent adducts. Previous studies have shown that genetic variations in metabolism and repair genes can mediate the sensitivity to butadiene-induced mutations and cancer. Because of the 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 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. In the previous funding period, we observed significant ethnic differences in the excretion of urinary butadiene-mercapturic acids by White, African American, Japanese American, and Native Hawaiian smokers. These results indicate that these ethnic groups metabolize butadiene differently due to genetic variations in biotransformation genes such as glutathione-S-transferase 1 (GSTT1). We now hypothesize that due to ethnic variations in butadiene metabolism, human populations of different ethnicity/race form different numbers of butadiene-DNA adducts, which contributes to ethnic disparities in cancer risk following exposure to butadiene in tobacco smoke. The objective of this application is to investigate inter-individual and inter-ethnic/racial differences in formation of butadiene- induced DNA adducts in smokers, to establish their role in lung cancer risk, and to link inter-individual differences in response to butadiene to specific polymorphisms of carcinogen metabolism and DNA repair genes. Our approach is innovative because we will, for the first time, examine butadiene-DNA adduct formation in a large multi-ethnic cohort of smokers, evaluate the association between butadiene exposure and lung cancer, and evaluate the effects of specific genetic polymorphisms on butadiene metabolism, DNA adduct formation, toxicity, and mutations in human HapMap cell cultures. Expected outcomes: Although smoking is a recognized risk factor for lung cancer, one out of five Americans continue to smoke. About 11-24 % of smokers will develop lung tumors over the lifetime, with a greater cancer incidence in African American and Native Hawaiian cigarette smokers as compared with European Americans, Japanese Americans, and Latinos. Our studies will help provide insight into the origins of this variability in sensitivity to smoking-mediated lung cancer and help identify individuals at risk who should be candidates for special smoking cessation intervention or chemopreventive therapy.