The main focus of our proposal is to understand the pharmacological basis for differences in individual susceptibility to tobacco addiction and adverse health and consequences of smoking, and to advance the science base relevant to tobacco harm reduction. Clinical studies will investigate genetic and environmental factors that influence nicotine metabolism and questions of the cardiovascular safety of nicotine. Using stable isotope methodology, we will characterize nicotine clearance and metabolism phenotype in African-Americans, Asian-Americans, and whites, and we will identify gene polymorphisms that underlie racial differences in nicotine metabolism. To examine the possible contribution of smoking mentholated cigarettes to tobacco-related disease, we will study exposure to tobacco smoke carcinogens and patterns of nicotine and tobacco-specific nitrosamine metabolism in African-Americans and whites, comparing those who smoke mentholated vs. regular cigarettes. To explore the mechanism of our prior observation that smoking mentholated cigarettes inhibits nicotine metabolism, we will examine the effects of dietary menthol on nicotine metabolism. To further our understanding of the observation that cigarette smoking inhibits nicotine metabolism, we will examine the effects of nicotine itself on nicotine metabolism (CYP2A6), and the effects on the metabolism of other drugs. We will examine the hypothesis that nicotine itself is metabolized in the body to the tobacco-specific nitrosamine NNAL. To examine nicotine cardiovascular safety issues, we will examine the effects of nicotine on various biomarkers of cardiovascular disease, including studies of transdermal nicotine vs. cigarette smoking, studies of the effects of smoking cigarettes with different nicotine content, and studies of the effects of concomitant transdermal nicotine and cigarette smoking. Chemistry studies will include: a) developing and executing GC-MS and LC-MS/MS assays for nicotine metabolites, tobacco smoke carcinogens, and various cardiovascular biomarkers for studies of nicotine metabolism and nicotine safety; b) synthesis of tobacco alkaloids, metabolites and deuterium-labeled analogs for pharmacological and metabolic studies. Our research program will help further define the role of nicotine and metabolites in the dependence process and will aid in the development of harm reduction approaches for tobacco addiction. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002277-28
Application #
7082958
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Rapaka, Rao
Project Start
1979-03-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
28
Fiscal Year
2006
Total Cost
$592,926
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
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
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
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; 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-Fran├žois; 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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