Understanding the metabolism, pharmacokinetics and pharmacodynamics of nicotine and other tobacco alkaloids will help define factors influencing smoking and its adverse effects and may lead to novel treatment approaches for tobacco addiction. We continue a research program combining synthetic and analytical chemistry and clinical investigation. Chemistry studies will include (a) developing methodology for quantitative analysis of tobacco alkaloids and metabolites and applying these methods to qualitatively and quantitatively define pathways of metabolism in humans. Particular emphasis will be placed on trans-3'-hydroxycotinine, which appears to be the major urinary metabolite of nicotine; (b) synthesis of tobacco alkaloids and stereoisomers, metabolites and deuterium-labeled analogs for pharmacologic and metabolic studies, and (c) developing GC-MS assays for nicotine metabolites and other tobacco alkaloids. Clinical studies will pursue extensions of the hypothesis that habitual smokers regulate body levels of nicotine; namely, (a) the rate of nicotine metabolism is an important determinant of individual differences in tobacco smoking behavior, and (b) administering nicotine in adequate levels or inhibiting nicotine metabolism will suppress self-determined intake of nicotine form smoking. Using stable isotope methodology, the kinetics of nicotine and cotinine, including measurement of percent conversion of nicotine to cotinine, and its relationship to daily intake of nicotine from smoking will be compared in men and women, young vs. old and smokers vs. nonsmokers. We will examine the influence of cigarette smoking per se on metabolism of nicotine. We will test the hypothesis that nonsmokers have significant response to nicotine at blood levels comparable to those seen after environmental tobacco smoke exposure. The influence of prolonged infusions of nicotine, dosed to fully replace levels of nicotine achieved by smoking, and of oral nicotine on daily intake of nicotine from smoking will be examined. The metabolism, kinetics and effects of (R)-nicotine, nornicotine and other tobacco alkaloids will be studied to see if these contribute to overall effects of cigarette smoking or interact with the metabolism or effects of natural (s)-nicotine. We will test whether (R)-nicotine influences smoking behavior and resultant effects. The proposed studies will clarify factor determining tobacco consumption and effects and may lead to more effective ways of treating tobacco addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA002277-10
Application #
3207232
Study Section
Drug Abuse Clinical and Behavioral Research Review Committee (DACB)
Project Start
1979-03-01
Project End
1993-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
10
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Overall Medical
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Taghavi, Taraneh; St Helen, Gideon; Benowitz, Neal L et al. (2017) Effect of UGT2B10, UGT2B17, FMO3, and OCT2 genetic variation on nicotine and cotinine pharmacokinetics and smoking in African Americans. Pharmacogenet Genomics 27:143-154
Gubner, Noah R; Kozar-Konieczna, Aleksandra; Szoltysek-Boldys, Izabela et al. (2016) Cessation of alcohol consumption decreases rate of nicotine metabolism in male alcohol-dependent smokers. Drug Alcohol Depend 163:157-64
Benowitz, Neal L; St Helen, Gideon; Dempsey, Delia A et al. (2016) Disposition kinetics and metabolism of nicotine and cotinine in African American smokers: impact of CYP2A6 genetic variation and enzymatic activity. Pharmacogenet Genomics 26:340-50
Baurley, James W; Edlund, Christopher K; Pardamean, Carissa I et al. (2016) Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries. Nicotine Tob Res 18:1837-1844
Ross, Kathryn C; Dempsey, Delia A; St Helen, Gideon et al. (2016) The Influence of Puff Characteristics, Nicotine Dependence, and Rate of Nicotine Metabolism on Daily Nicotine Exposure in African American Smokers. Cancer Epidemiol Biomarkers Prev 25:936-43
Benowitz, Neal L; Nardone, Natalie; Dains, Katherine M et al. (2015) Effect of reducing the nicotine content of cigarettes on cigarette smoking behavior and tobacco smoke toxicant exposure: 2-year follow up. Addiction 110:1667-75
Wassenaar, Catherine A; Conti, David V; Das, Soma et al. (2015) UGT1A and UGT2B genetic variation alters nicotine and nitrosamine glucuronidation in european and african american smokers. Cancer Epidemiol Biomarkers Prev 24:94-104
Shiffman, Saul; Dunbar, Michael S; Benowitz, Neal L (2014) A comparison of nicotine biomarkers and smoking patterns in daily and nondaily smokers. Cancer Epidemiol Biomarkers Prev 23:1264-72
Hajek, Peter; Etter, Jean-François; Benowitz, Neal et al. (2014) Electronic cigarettes: review of use, content, safety, effects on smokers and potential for harm and benefit. Addiction 109:1801-10
Leventhal, Adam M; Lee, Wonho; Bergen, Andrew W et al. (2014) Nicotine dependence as a moderator of genetic influences on smoking cessation treatment outcome. Drug Alcohol Depend 138:109-17

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