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Nicotine Metabolism in Families

Institution: University of California, San Francisco
Investigator(s): Neal Benowitz, M.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7PT-2004 Award: $465,537
Subject Area: Epidemiology
Award Type: Integrated Research Project

Initial Award Abstract
A recent report in the scientific literature indicates that certain differences in the DNA (gene) that controls the speed at which nicotine is disposed of in the human body may help to determine whether individuals become smokers. This finding, if confirmed, could have an important effect on the prevention and treatment of nicotine addiction. To date, however, there are no independent confirmations of this finding. Moreover, the authors of this report did not provide evidence that the variations in the gene were, in fact, related to differences in nicotine metabolism.

The proposed investigation seeks to further examine the issue of whether genetic differences lead to susceptibility to become a smoker through: (1) the administration of an oral dose of cotinine, a chemical related to nicotine, to members of 250 families; (2) collection of urine over 8 hours and saliva over 60 hours following cotinine administration; and (3) assays for cotinine and metabolites using advanced laboratory methods. We will then determine if the genetic differences are related to smoking behavior and how people metabolize cotinine, and if specific genes are related to cigarette consumption, level of nicotine dependence, and other factors.

We will use state-of-the-art methodology to define cotinine metabolism. The successful completion of this study will provide an exciting opportunity to examine the relationship between this advanced biological index of nicotine addiction and other, less precise, measures of nicotine addiction.

Nicotine metabolite ratio as a predictor of CYP2A6 phenotypic activity.
Periodical: Clinical Pharmacology and Therapeutics Index Medicus:
Authors: Dempsey DA, Tutka P, Jacob P, and Benowitz NL ABS
Yr: 2002 Vol: 71 Nbr: Abs: Pg: 24

Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity.
Periodical: Clinical Pharmacology and Therapeutics Index Medicus:
Authors: Dempsey D, Tutka P, Jacob P, et al. ART
Yr: 2004 Vol: 76 Nbr: 1 Abs: Pg: 64 - 72