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.
Although smoking is a recognized risk factor for lung cancer, one out of five Americans continue to smoke. About 15% of smokers will develop lung cancer 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.
|Patel, Yesha M; Stram, Daniel O; Wilkens, Lynne R et al. (2015) The contribution of common genetic variation to nicotine and cotinine glucuronidation in multiple ethnic/racial populations. Cancer Epidemiol Biomarkers Prev 24:119-27|
|Zarth, Adam T; Carmella, Steven G; Le, Chap T et al. (2014) Effect of cigarette smoking on urinary 2-hydroxypropylmercapturic acid, a metabolite of propylene oxide. J Chromatogr B Analyt Technol Biomed Life Sci 953-954:126-31|
|Kotapati, Srikanth; Sangaraju, Dewakar; Esades, Amanda et al. (2014) Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species. Carcinogenesis 35:1371-8|
|Park, Sungshim Lani; Kotapati, Srikanth; Wilkens, Lynne R et al. (2014) 1,3-Butadiene exposure and metabolism among Japanese American, Native Hawaiian, and White smokers. Cancer Epidemiol Biomarkers Prev 23:2240-9|
|Jing, Meng; Wang, Yaohua; Upadhyaya, Pramod et al. (2014) Liquid chromatography-electrospray ionization-tandem mass spectrometry quantitation of urinary [pyridine-D4]4-hydroxy-4-(3-pyridyl)butanoic acid, a biomarker of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolic activation in smokers. Chem Res Toxicol 27:1547-55|
|Murphy, Sharon E; Park, Sung-Shim L; Thompson, Elizabeth F et al. (2014) Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups. Carcinogenesis 35:2526-33|
|Sangaraju, Dewakar; Villalta, Peter W; Wickramaratne, Susith et al. (2014) NanoLC/ESI+ HRMS3 quantitation of DNA adducts induced by 1,3-butadiene. J Am Soc Mass Spectrom 25:1124-35|
|Narayanapillai, Sreekanth C; Balbo, Silvia; Leitzman, Pablo et al. (2014) Dihydromethysticin from kava blocks tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis and differentially reduces DNA damage in A/J mice. Carcinogenesis 35:2365-72|
|Zhang, Jianqi; Stram, Daniel O (2014) The role of local ancestry adjustment in association studies using admixed populations. Genet Epidemiol 38:502-15|
|Carmella, Steven G; Ming, Xun; Olvera, Natalie et al. (2013) High throughput liquid and gas chromatography-tandem mass spectrometry assays for tobacco-specific nitrosamine and polycyclic aromatic hydrocarbon metabolites associated with lung cancer in smokers. Chem Res Toxicol 26:1209-17|
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