Article

Genetic variability in CYP2A6 and the pharmacokinetics of nicotine

University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
Pharmacogenomics (Impact Factor: 3.43). 11/2007; 8(10):1385-402. DOI: 10.2217/14622416.8.10.1385
Source: PubMed

ABSTRACT Nicotine is the psychoactive substance responsible for tobacco dependence. It is also a therapeutic used to aid smoking cessation. Cytochrome P450 (CYP)2A6 is the human hepatic enzyme that mediates most of nicotine's metabolic inactivation to cotinine. Genetic variation in the CYP2A6 gene can increase or decrease enzyme activity through altering the protein's expression level or its structure and function. This article reviews CYP2A6 genetic variation and its impact on in vivo nicotine kinetics, including a description of the individual variants, different phenotyping approaches for assessing in vivo CYP2A6 activity and other sources of variation in nicotine metabolism such as gender. In addition, the effect of CYP2A6 polymorphisms on smoking behavior and tobacco-related lung cancer risk are briefly described. Furthering knowledge in this area will improve interpretation of studies examining smoking behavior, as well as those using nicotine as a therapeutic agent.

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    • "In addition to CYP2A6, nicotine is inactivated by other oxidative (e.g., flavin-containing mono-oxygenase 3) and nonoxidative (e.g., uridine diphosphate-glucuronosyltransferase) enzymes, and the influences of polymorphisms in the genes in these pathways are under investigation. For additional detail, see these reviews: Balfour, 2002; Benowitz, Hukkanen, & Jacob, 2009; Di Chiara, 2000; Hukkanen, Jacob, & Benowitz, 2005; Laviolette & van der Kooy, 2004; Mwenifumbo & Tyndale, 2007; Stolerman & Shoaib, 1991; Watkins, Koob, & Markou, 2000. Preclinical Models Provide Insights Into Individual Differences in Nicotine-Induced Behavior Preclinical models as conventionally defined entail " research using animals to find out if a drug, procedure, or treatment is likely to be useful, " which takes place prior to testing in humans (National Cancer Institute, 2010). "
    Handbook of Psychology, Health Psychology, Edited by Nezu, A, Nezu, C, Geller, PA, Weiner, I, 01/2013: chapter Nicotine Dependence: pages 149-181; John Wiley & Sons.
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    • "Thus, slow metabolizers smoke fewer cigarettes daily and weekly and have lower CO and plasma nicotine levels, suggesting a reduced smoking rate compared with normal metabolizers (Levi et al. 2007; Mwenifumbo and Tyndale 2007). Conversely, higher CYP2A6 activity is associated with greater cigarette consumption (Mwenifumbo et al. 2007). "
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