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.
|Murphy, Sharon E; von Weymarn, Linda B; Parenteau, Marc et al. (2018) Influence of UGT2B10 Genotype on Urinary Excretion of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol- N-glucuronide by African American Smokers. Chem Res Toxicol 31:168-175|
|Degner, Amanda; Carlsson, Henrik; Karlsson, Isabella et al. (2018) Discovery of Novel N-(4-Hydroxybenzyl)valine Hemoglobin Adducts in Human Blood. Chem Res Toxicol :|
|Park, Sungshim L; Patel, Yesha M; Loo, Lenora W M et al. (2018) Association of internal smoking dose with blood DNA methylation in three racial/ethnic populations. Clin Epigenetics 10:110|
|Murphy, Sharon E; Park, Sungshim Lani; Balbo, Silvia et al. (2018) Tobacco biomarkers and genetic/epigenetic analysis to investigate ethnic/racial differences in lung cancer risk among smokers. NPJ Precis Oncol 2:17|
|Chai, Weiwen; Morimoto, Yukiko; Cooney, Robert V et al. (2017) Dietary Red and Processed Meat Intake and Markers of Adiposity and Inflammation: The Multiethnic Cohort Study. J Am Coll Nutr 36:378-385|
|Park, Sungshim L; Murphy, Sharon E; Wilkens, Lynne R et al. (2017) Association of CYP2A6 activity with lung cancer incidence in smokers: The multiethnic cohort study. PLoS One 12:e0178435|
|Murphy, Sharon E (2017) Nicotine Metabolism and Smoking: Ethnic Differences in the Role of P450 2A6. Chem Res Toxicol 30:410-419|
|Boldry, Emily J; Patel, Yesha M; Kotapati, Srikanth et al. (2017) Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer. Cancer Epidemiol Biomarkers Prev 26:1034-1042|
|Sangaraju, Dewakar; Boldry, Emily J; Patel, Yesha M et al. (2017) Isotope Dilution nanoLC/ESI+-HRMS3 Quantitation of Urinary N7-(1-Hydroxy-3-buten-2-yl) Guanine Adducts in Humans and Their Use as Biomarkers of Exposure to 1,3-Butadiene. Chem Res Toxicol 30:678-688|
|Peterson, Lisa A (2017) Context Matters: Contribution of Specific DNA Adducts to the Genotoxic Properties of the Tobacco-Specific Nitrosamine NNK. Chem Res Toxicol 30:420-433|
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