Tobacco use is responsible for 90% of all lung cancers. A large prospective study carried out by the investigators of Project 1 of this POI reported a 2-5 fold difference among US racial/ethnic minorities in the risk of lung cancer due to cigarette smoking. The overall hypothesis of this program project grant is that this differential cancer risk is due to dissimilarities in exposure and response to tobacco smoke carcinogens. The exposure of a smoker to tobacco carcinogens is driven by nicotine addiction. Their response to nicofine and to most carcinogens is directiy influenced by the metabolism of these compounds. Two key routes of nicotine and carcinogen metabolism are P450-catalyzed oxidation and UGT-catalyzed conjugation. 4- (Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco specific nitrosamine, is a designated human carcinogen. It is the overall goal of this project to characterize racial/ethnic differences in the glucuronidation pathway of nicotine and NNK metabolism and to determine the SNPs present in UGTs associated with these differences. Three glucuronidation pathways will be studied: nicofine glucuronidation, and the glucuronidation oftwo NNK metabolites, NNAL and a-hydroxymethylNNK. The pathways will be assessed by urinary levels of glururonide metabolites and UGT variants will be characterized in vitro. Our preliminary data provided evidence of lower nicotine glucuronidation in African Americans relative to European Americans, and this project will focus on these two groups. However, through interactions with the large genome wide association study of carcinogen exposure and metabolism in project 1 we will extend our studies to other ethnic/racial groups.
Our aims are to confirm the observed ethnic/racial difference in nicotine glucuronidation, and to extend our studies to NNAL glucuronidation. We will test the hypothesis that the extent of NNAL /V-glucuronidation is lower in racial/ethnic groups with a higher risk of smoking related lung cancer. NNAL glucuronidation is a key detoxification pathway of NNK. In the rat we have identified a 2""""""""'^ potentially more important NNK detoxification pathway, glucuronidation of a-hydroxymethylNNK. In the last two aims of this project we will develop the methodology to quantify this glucuronide in smokers and to test our hypothesis that its formation in smokers is critical to the regulation of DNA adduct formation and potentially cancer risk.

Public Health Relevance

Lung cancer is the leading cause of cancer deaths woridwide. This POI examines the genetic factors that affect how people smoke and respond to carcinogens. The mechanistic understanding of how variations in UGT activity/expression affect the metabolism of nicotine and NNK strengthens any association between UGTs and lung cancer identified and will provide targets for smoking cessafion and lung cancer prevention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-7)
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University of Minnesota Twin Cities
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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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