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

项目 3 - 1,3-丁二烯代谢和 DNA 加合物形成的民族/种族差异

基本信息

批准号：
9538595
负责人：
NATALIA Y TRETYAKOVA
金额：
$ 20.22万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9538595
关键词：
1,3-Butadiene Acetylcysteine Affect African American American Binding Biological Butadiene Butylene Glycols Cancer Etiology Carcinogen Metabolism Carcinogens Cell Culture Techniques Cells Characteristics Chemicals Chemopreventive Agent Cigarette Smoker Code Collaborations DNA DNA Adduction DNA Adducts DNA Damage DNA Modification Process DNA Repair DNA Repair Gene Development Drug Metabolic Detoxication Enzymes Epidemiology Epoxide hydrolase Epoxy Compounds Ethnic Origin Ethnic group European Excretory function Exposure to Frequencies Funding Genes Genetic Polymorphism Genetic Variation Genotype Glutathione Glutathione S-Transferase Goals Guanine Hematopoietic Neoplasms High Pressure Liquid Chromatography High-Risk Cancer Homeostasis Human Human Herpesvirus 4 Hydrolysis Incidence Individual Individual Differences Induced Mutation Inhalation Japanese American Japanese Population KRAS2 gene Laboratory Animals Laboratory mice Latino Link Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Metabolic Metabolic Activation Metabolic Biotransformation Metabolism Methodology Molecular Mutagenesis Mutation Native Hawaiian Occupational Exposure Oncogenes Outcome Physiological Population Positioning Attribute Predisposition Race Risk Risk Assessment Risk Factors Role Sampling Smoke Smoker Smoking Smoking Cessation Intervention TP53 gene Testing Time Tobacco smoke Toxic effect Toxicology Urine Variant adduct base cancer health disparity cancer initiation cancer risk carcinogenesis caucasian American cigarette smoke cigarette smoking clinical biomarkers cohort erythritol anhydride ethnic difference ethnic disparity gene repair indexing innovation insight inter-individual variation lymphoblastoid cell line mortality non-smoker nucleobase professor racial and ethnic racial difference repaired response true biomarker urinary

项目摘要

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.

摘要