A number of biological factors may influence an individual's smoking behavior. These include a smoker's sensitivity to and metabolism of nicotine. Specifically, we will determine if different parameters of nicotine metabolism are predictors of tobacco consumption and nicotine addiction. These parameters include: 1) P0450 2A6 phenotype 2) nicotine metabolism to continue; 3) nicotine metabolism by N-glucuronidation and N-oxidation. The major pathway of nicotine metabolism is conversion to cotinine, and there is strong in vitro data supporting a key role for P450 2AG phenotype 2) nicotine metabolism is cotinine; 3) nicotine metabolism by N-glucoronidation and N-oxidation. The major pathway of nicotinine metabolism is conversion to cotinine, and there is strong in vitro data supporting a key role for P450 2A6 as the catalyst of the first step in this pathway. P450 2A6 activity varies significantly between people. Therefore, P450 2A6 is an attractive candidate both as a key enzyme in nicotine addiction. These parameters include: 1) P450 2A6 phenotype 2) nicotine metabolism to cotinine; 3) nicotine metabolism by N-glucoronidation and oxidation. The major pathway of nicotine metabolism is conversion to cotinine, and there is strong in vitro data supporting a key role for P450 2A6 as the catalyst of the first step in this pathway. P450 2A6 activity varies significantly between people. Therefore, P450 2A6 is an attractive candidate both as a key enzyme in nicotine metabolism in smokers and as an important biological determinant of tobacco consumption and nicotine addiction. It is our hypothesis that an individual's ability to metabolize nicotine does influence tobacco consumption and thereby there sensitivity to related to nicotine addiction. Within a population of addicted smokers there is a wide range of cigarette consumption and nicotine addiction. It is our hypothesis that an individual's ability to metabolize nicotine does influence tobacco consumption and thereby there sensitivity to related to nicotine addiction. Within a population of addicted smokers there is a wide range of cigarette consumption. We hypothesize that some of this variation is due to differences in metabolism and that tobacco consumption influences nicotine addiction. In our Aims we will test this hypothesis, and the hypothesis that P450 2A6 is a key enzyme in nicotine metabolism but not the only enzyme responsible for the proposed relationship between nicotine addiction and metabolism.
Our Specific Aims are to determine: 1) the correlation between the rate of nicotine clearance (following infusion) and P450 2A6 phenotype, 2) if a smoker's P450 phenotype predicts their urinary nicotine metabolite profile, 3) the relationship of either P450 2A6 phenotype or nicotine profile to tobacco consumption and nicotine addiction, and 4) whether an individual's nicotine metabolite profile and/or P4502A6 phenotype is a determinant of the familial distribution of tobacco consumption and nicotine addiction.
Aim 4 will carry out a sibling pair analysis of nicotine metabolism tobacco consumption and nicotine addiction to investigate the degree to which metabolism contributes to the familiarity of tobacco consumption and nicotine addiction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA089392-02
Application #
6654072
Study Section
Subcommittee E - Prevention &Control (NCI)
Project Start
2002-09-01
Project End
2003-08-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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