African-Americans are a particularly vulnerable group of smokers who experience high levels of addiction and smoking-related disease risk compared to whites, yet there has been little systematic research in this area. Our proposal seeks to clarify the nature of racial differences in smoking behavior and exposure to tobacco smoke toxins (African-Americans vs whites), and their relationship to differences in the pharmacology of nicotine (metabolism and reinforcement). An ultimate objective is to use this knowledge to aid in the development of more effective smoking cessation interventions for African-Americans. Four studies are proposed: #1: We will first use stable isotope methodology to characterize nicotine metabolic pathways, and will then determine the association (in African-Americans) of metabolism/PK phenotypes with genetic polymorphisms in the genes responsible for nicotine metabolism. #2: We will compare changes in smoking behavior, extent of nicotine titration, and tobacco smoke toxin exposure that result from switching from regular yield to light cigarettes in African-Americans vs. whites. We hypothesize that African-Americans smoke in a manner to get positive reinforcement (nicotine peak-seekers) more than do whites, who are hypothesized to smoke in a manner to maintain nicotine levels throughout the day (nicotine trough-maintainers), and that this will influence the response to switching. #3, 4: We will examine the effects of acute administration (single dose) vs. longer term (7 day) treatment with smoking cessation medications on smoking behavior, reinforcement and tobacco smoke toxin exposure. We propose that African-American and white smokers will respond differently to two medications with different mechanisms of action (transdermal nicotine and varenicline). Secondary analyses using data pooled across studies will examine the relationship of smoking behaviors and tobacco smoke toxin intake to each of these elements: (a) nicotine clearance, (b) use of menthol vs. non-menthol cigarettes and (c) motivations for smoking and dependence measures. Chemistry activities will include (1) synthesis of stable isotope-labeled compounds, including nicotine, cotinine and 3-hydroxy-cotinine for quantitative metabolic studies;and (2) developing and applying GC- MS and LC-MS/MS methods to quantify nicotine and metabolites and tobacco smoke carcinogens for metabolism and exposure assessment studies. Narrative African-Americans are a particularly vulnerable group of smokers who experience high levels of addiction and smoking-related disease risk compared to whites, yet there has been little systematic research in this area. Our proposal seeks to clarify the nature of racial differences in smoking behavior and exposure to tobacco smoke toxins (African-Americans vs whites), and their relationship to differences in the pharmacology of nicotine (metabolism and reinforcement). An ultimate objective is to use this knowledge to aid in the development of more effective smoking cessation interventions for African-Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002277-34
Application #
8287138
Study Section
Special Emphasis Panel (ZRG1-DIG-B (02))
Program Officer
Purohit, Vishnudutt
Project Start
1979-03-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
34
Fiscal Year
2012
Total Cost
$619,380
Indirect Cost
$196,326
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
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
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
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
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
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
Dempsey, D A; Sambol, N C; Jacob 3rd, P et al. (2013) CYP2A6 genotype but not age determines cotinine half-life in infants and children. Clin Pharmacol Ther 94:400-6
St Helen, Gideon; Jacob 3rd, Peyton; Benowitz, Neal L (2013) Stability of the nicotine metabolite ratio in smokers of progressively reduced nicotine content cigarettes. Nicotine Tob Res 15:1939-42

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