Cigarette smoking causes approximately 30% of all cancer death in the U.S. It is responsible for 85% of the 160,000 lung cancer deaths expected in 1998. Snuff-dipping is an acknowledged cause of oral cavity cancer and the use of moist snuff in the U.S. has increased remarkably in recent years. In spite of advances in tobacco control and smoking cessation, there are still 48 million smokers in the U.S., about 25% of the adult population. Approximately 500 billion cigarettes and 121 million pounds of smokeless tobacco were consumed in 1997 in the U.S. Tobacco-specific N-nitrosamines are formed from tobacco alkaloids during the curing and processing of tobacco products. Two of these, 4- (methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) and N- nitrosonornicotine (NNN), are present in substantial quantities and are strong carcinogens. NNK is a potent pulmonary carcinogen in rodents and also induces tumors of the pancreas, nasal mucosa, and liver. NNN causes tumors of the esophagus and nasal mucosa in rats and respiratory tract tumors in mice and hamsters. A mixture of NNK and NNN induces oral tumors in rats. Based on their carcinogenic activities, the extensive data on the occurrence of NNK and NNN in tobacco products, and on biochemical studies, it is our hypothesis that these compounds play a significant role as causative factors in human cancers associated with tobacco use. Although there are parallels between NNK and NNN metabolism in rodents and humans which support our hypothesis, there are key aspects which must be explored to further evaluate our hypothesis. Therefore, our specific aims are: 1) investigate stereoselectivity on the metabolism of NNK and NNN by delineating differences in the formation and further metabolism of enantiomers of the major NNK metabolite NNAL, determining differences in the stereoselectivity of metabolic activation of NNK, and examining differences in the metabolic activation and carcinogenicity of NNN enantiomers; 2) investigate DNA and protein pyridyloxo-butylation by NNK and NNN by elucidating the structures of the major adducts formed with DNA and hemoglobin; and 3) investigate the metabolism of NNK and NNN in humans by determining levels of NNN metabolites in human urine, characterizing previously unknown NNN metabolites, and examining NNK metabolites in the urine of snuff-dippers to determine their persistence after cessation and their amounts as a function of dose. The overall theme of this proposal is mechanistic studies of NNK and NNN metabolism and adduct formation, in order to further evaluate the carcinogenic potential of NNK and NNN in humans exposed to tobacco products. We believe that an understanding of the mechanisms by which tobacco smoke carcinogens cause cancer will lead to new insights on individual cancer susceptibility and development of innovative strategies to prevent tobacco related cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA081301-05
Application #
6628195
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
1999-04-01
Project End
2004-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
5
Fiscal Year
2003
Total Cost
$386,106
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Kovi, Ramesh C; Johnson, Charles S; Balbo, Silvia et al. (2018) Metastasis to the F344 Rat Pancreas from Lung Cancer Induced by 4-(Methylnitrosamino)- 1-(3-pyridyl)-1-butanone and Enantiomers of Its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)- 1-butanol, Constituents of Tobacco Products. Toxicol Pathol 46:184-192
Ma, Bin; Zarth, Adam T; Carlson, Erik S et al. (2018) Methyl DNA Phosphate Adduct Formation in Rats Treated Chronically with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and Enantiomers of Its Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol. Chem Res Toxicol 31:48-57
Upadhyaya, Pramod; Zarth, Adam T; Fujioka, Naomi et al. (2018) Identification and analysis of a mercapturic acid conjugate of indole-3-methyl isothiocyanate in the urine of humans who consumed cruciferous vegetables. J Chromatogr B Analyt Technol Biomed Life Sci 1072:341-346
Ma, Bin; Zarth, Adam T; Carlson, Erik S et al. (2018) Identification of more than 100 structurally unique DNA-phosphate adducts formed during rat lung carcinogenesis by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 39:232-241
Ma, Bin; Zarth, Adam T; Carlson, Erik S et al. (2017) Pyridylhydroxybutyl and pyridyloxobutyl DNA phosphate adduct formation in rats treated chronically with enantiomers of the tobacco-specific nitrosamine metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol. Mutagenesis 32:561-570
Michel, Anna K; Zarth, Adam T; Upadhyaya, Pramod et al. (2017) Identification of 4-(3-Pyridyl)-4-oxobutyl-2'-deoxycytidine Adducts Formed in the Reaction of DNA with 4-(Acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone: A Chemically Activated Form of Tobacco-Specific Carcinogens. ACS Omega 2:1180-1190
Yang, Jing; Carmella, Steven G; Hecht, Stephen S (2017) Analysis of N'-nitrosonornicotine enantiomers in human urine by chiral stationary phase liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 1044-1045:127-131
Carlson, Erik S; Upadhyaya, Pramod; Hecht, Stephen S (2017) A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s. J Vis Exp :
Hecht, Stephen S (2017) Oral Cell DNA Adducts as Potential Biomarkers for Lung Cancer Susceptibility in Cigarette Smokers. Chem Res Toxicol 30:367-375

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