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
Mercati, O; Huguet, G; Danckaert, A et al. (2017) CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders. Mol Psychiatry 22:625-633
Wang, Jian; Talluri, Rajesh; Shete, Sanjay (2017) Selection of X-chromosome Inactivation Model. Cancer Inform 16:1176935117747272
Teitelbaum, A M; Murphy, S E; Akk, G et al. (2017) Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain. Pharmacogenomics J :
Zhang, Tian-Xiao; Saccone, Nancy L; Bierut, Laura J et al. (2017) Targeted sequencing identifies genetic polymorphisms of flavin-containing monooxygenase genes contributing to susceptibility of nicotine dependence in European American and African American. Brain Behav 7:e00651
Singh, Tarjinder; Walters, James T R; Johnstone, Mandy et al. (2017) The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat Genet 49:1167-1173
Peckham-Gregory, Erin C; Chakraborty, Rikhia; Scheurer, Michael E et al. (2017) A genome-wide association study of LCH identifies a variant in SMAD6 associated with susceptibility. Blood 130:2229-2232
Hancock, D B; Guo, Y; Reginsson, G W et al. (2017) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry :
Wang, Minghui; Huang, Jianfei; Liu, Yiyuan et al. (2017) COMBAT: A Combined Association Test for Genes Using Summary Statistics. Genetics 207:883-891
Taylor, Kimberly E; Wong, Quenna; Levine, David M et al. (2017) Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren's Syndrome According to Ancestry. Arthritis Rheumatol 69:1294-1305
Hartz, Sarah M; Horton, Amy C; Oehlert, Mary et al. (2017) Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia. Biol Psychiatry 82:709-715

Showing the most recent 10 out of 253 publications