Genetic variability in CYP2A6 and the pharmacokinetics of nicotine
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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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.
- "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). "
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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). "
ABSTRACT: Growing proportions of smokers in the USA do not smoke everyday and can be referred to as light and intermittent smokers (LITS). Despite a current prevalence of LITS in the USA estimated at 25-33% of all smokers, a systematic review of the literature on this group of smokers has yet to be written. The aim of this paper is to review and evaluate research on LITS and to identify, describe and discuss commonalities and differences between LITS and daily smokers. The primary databases used to search for publications were Pub Med (National Library of Medicine) and SCOPUS (Elsevier). LITS inhale smoke and have post-smoking blood nicotine concentrations that are broadly equivalent to those found in daily smokers. However, LITS differ from daily smokers with regard to cigarette consumption and frequency of cigarette use, sociodemographic and socioeconomic characteristics, motives, personality traits, dependence, withdrawal and craving, response to smoking-related cues, quitting perception, past-smoking status, and initiation. In contrast to daily smokers, LITS show few or no signs of dependence as currently defined by DSM-IV criteria, appear to exercise more self-control, seem to be less impulsive, and their smoking experience is primarily associated with positive rather than negative reinforcement. Conclusions drawn from the reviewed literature highlight the multivariate factors that must be taken into account when defining LITS and emphasize the importance of further research on this increasing fraction of smokers. The potential implications of increased LITS prevalence on smoking-related disease risks remain to be thoroughly investigated.Psychopharmacology 10/2009; 207(3):343-63. DOI:10.1007/s00213-009-1675-4 · 3.99 Impact Factor