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

1, 3-联二烯代谢和 DNA 加合物形成的民族/种族差异

基本信息

批准号：
7786638
负责人：
NATALIA Y TRETYAKOVA
金额：
$ 13.66万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7786638
关键词：
1,3-Butadiene 3,4-epoxy-1-butene Acetylcysteine African African American American Binding Biological Biological Markers Breathing Butadiene Butane Butanes Butylene Glycols CYP2E1 gene Cancer Etiology Carcinogen Metabolism Carcinogens Chemicals Chemopreventive Agent Chromosome abnormality Cigarette Cigarette Smoker Code Cytochrome P450 DNA Adduction DNA Adducts DNA Damage DNA Modification Process DNA Repair Gene Diet Habits Dose Drug Metabolic Detoxication EPHX1 gene Employee Strikes Enzymes Epidemiology Epoxide hydrolase Epoxy Compounds Ethics Ethnic Origin Ethnic group European Excretory function Exhibits Exposure to Frequencies Future GSTT1 gene Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Glutathione Glutathione S-Transferase Glycols Goals Harderian Gland Hawaiian population Heart Human Hydrolysis Incidence Individual Japanese American Laboratory Animals Latino Link Liver Lung Lung Neoplasms Lymphatic Mainstreaming Malignant Neoplasms Malignant neoplasm of lung Mammary gland Mediating Metabolic Activation Metabolic Biotransformation Metabolism Methods Molecular Mus Mutagenesis Mutation Neoplasms Ovary Pathway interactions Pattern Play Population Predisposition Prevalence Race Rattus Relative (related person)Research Risk Risk Factors Role Sampling Site Small-Cell Lymphoma Smoke Smoker Smoking Smoking Cessation Intervention Socioeconomic Factors Testing Time Tobacco smoke United States Urine Xenobiotics adduct base cancer risk carcinogenesis cigarette smoking cohort erythritol anhydride gene repair genotoxicity innovation insight mortality racial difference racial/ethnic difference species difference tumor initiation urinary

项目摘要

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.

丁二烯是一种重要的烟草烟雾致癌物质，可能与肺部肿瘤的诱发有关在吸烟者中。根据流行病学证据，丁二烯被列为已知的人类致癌物表明职业接触工人的癌症发病率增加以及吸入研究实验动物。丁二烯介导的致癌过程中公认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。之前的研究有研究表明，代谢和修复基因的遗传变异可以介导对丁二烯诱导的敏感性突变和癌症。由于丁二烯的代谢活化需要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诱变和致癌作用的敏感性。许多突出的多态性编码丁二烯代谢酶的基因，例如CYP2E1、EPHX1。和 GSTT1，已被鉴定。由于其频率在种族/种族群体之间存在差异，这些基因变化可能会导致观察了肺癌发病率的种族间/种族间差异。未来的研究有必要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中的代谢和生物效应。我们假设不同种族/种族的人群对丁二烯的代谢存在差异，接触烟草烟雾中的丁二烯后会导致不同程度的癌症风险。本申请的目的是研究丁二烯代谢和丁二烯诱导的 DNA 加合物形成中的个体间和种族/种族差异，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。这里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，并确定遗传多态性对丁二烯衍生环氧化物的遗传毒性的影响。我们的方法是创新的，因为我们将首次在一个大型多种族队列中分析民族/种族对丁二烯代谢和 DNA 加合物形成的影响。