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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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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