Lung cancer is the leading cause of cancer mortality in the U.S. and woridwide with the majority of these cancers caused by smoking. The Multiethnic Cohort (MEC) study strongly demonstrated that there are major differences among US ethnic/racial groups in lung cancer risk associated with smoking. We will investigate the hypothesis that African Americans are more susceptible to the carcinogenic properties of tobacco-associated chemicals than European Americans as a result of reduced DNA repair capacity. This will be assessed by determining the sensitivity of lymphocytes from Africans or African Americans and European Americans to the toxic and mutagenic activity of activated forms ofthe three tobacco carcinogens, 4 (methylnitrosamino)-l-(S pyridyl)-1 butanone, benzo[a]pyrene and 1,S-butadiene. We will test our hypothesis by performing the following specific aims: 1. Determine if there is a difference in sensitivity between European Americans and Africans to the cytotoxic effects of activated tobacco smoke carcinogens using the International HapMap Epstein-Barr virus (EBV)-transformed B-lymphocyte cell lines derived from trios of European Americans (CEU) and Yoruban (African, YRI) populations;2. Determine if there is a difference in sensitivity between European Americans and Africans to the genotoxic effects of activated tobacco smoke carcinogens using the HapMap B-lymphocyte cell lines;3. Determine if there is a difference in repair rates for tobacco smoke-derived carcinogen DNA adducts between European Americans and Africans using the HapMap lymphocyte cell lines or lymphocytes isolated from European American and African American smokers in Project 5;4. Perform candidate gene and genome-wide association studies of the toxicological phenotypes measured in Aims 1-3 to determine if specific genotypes drive the observed phenotypes in collaboration with Project 1. Collectively, these studies will reveal if there are ethnic/racial differences in repair of tobacco carcinogen derived DNA damage and if these differences in repair translate into differences in sensitivity to the genotoxic effects of these chemicals.
DNA repair is a critical step in the protection of a cell against the genotoxic effects of tobacco-carcinogens. Genetic variations in the proteins involved in these multiple step process influence how a cell responds to a gentoxic insult. Characterization genetic variations responsible for this decreased risk will allow for the identification of at risk individuals and allow the development of eariy detection and prevention strategies.
|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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