The Role of CYP2A6 in the Emergence of Nicotine Dependence in Adolescents

University of Toronto, Toronto, Ontario, Canada
PEDIATRICS (Impact Factor: 5.47). 02/2007; 119(1):e264-74. DOI: 10.1542/peds.2006-1583
Source: PubMed

ABSTRACT The objectives of our study were to evaluate whether genetic variation in nicotine metabolic inactivation accounted for the emergence of nicotine dependence from mid- to late adolescence and whether initial smoking experiences mediated this effect.
Participants were 222 adolescents of European ancestry who participated in a longitudinal cohort study of the biobehavioral determinants of adolescent smoking. Survey data were collected annually from grade 9 to the end of grade 12. Self-report measures included nicotine dependence, smoking, age first smoked, initial smoking experiences, peer and household member smoking, and alcohol and marijuana use. DNA collected via buccal swabs was assessed for CYP2A6 alleles that are common in white people and are demonstrated to decrease enzymatic function (CYP2A6*2, *4, *9, *12).
Latent growth-curve modeling indicated that normal metabolizers (individuals with no detected CYP2A6 variants) progressed in nicotine dependence at a faster rate and that these increases in nicotine dependence leveled off more slowly compared with slower metabolizers (individuals with CYP2A6 variants). Initial smoking experiences did not account for how CYP2A6 genetic variation impacts nicotine dependence.
These findings may help to promote a better understanding of the biology of smoking behavior and the emergence of nicotine dependence in adolescents and inform future work aimed at understanding the complex interplay between genetic, social, and psychological factors in adolescent smoking behavior.

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Available from: Daniel Rodriguez, Mar 28, 2014
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    • "As such, nicotine clearance is expected to be decreased and doses required to experience the rewarding and aversive effects of the drug would be lower (e.g., leftward shift of the doseeresponse curve). Consistent with this prediction, individuals with a slow metabolizer CYP2A6 genotype are less vulnerable to develop tobacco dependence than those with normal metabolism (Audrain-McGovern et al., 2007; Bloom et al., 2011; Thorgeirsson et al., 2010), potentially due to a greater sensitivity to aversive effects of nicotine at doses that do not trigger aversion in those who metabolize nicotine normally. Further supporting this notion, slow metabolizers consume less nicotine per day and are more successful when attempting to quit smoking than individuals with normal metabolism (Patterson et al., 2008; Rodriguez et al., 2011; Strasser et al., 2007). "
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    ABSTRACT: Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action is considered critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be proposed. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered.
    Neuropharmacology 09/2013; 76. DOI:10.1016/j.neuropharm.2013.09.008 · 5.11 Impact Factor
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    • "Increasing evidence suggests that nicotine dependence symptoms are substantially heritable [30,59,60]. The identification of nicotine dependence phenotypes may facilitate future research on genetic causes of behaviour, such as by testing the different phenotypes for an association with a particular genetic factor. "
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    ABSTRACT: Although several studies have reported that symptoms of nicotine dependence can occur after limited exposure to smoking, the majority of research on nicotine dependence has focused on adult smokers. Insufficient knowledge exists regarding the epidemiology and aetiology of nicotine dependence among adolescent smokers. The objective of the present study is to identify the effects of theoretically driven social and individual predictors of nicotine dependence symptom profiles in a population-based sample of adolescent smokers. A longitudinal study among 6,783 adolescents (12 to 14 years old at baseline) was conducted. In the first and second year of secondary education, personality traits and exposure to smoking in the social environment were assessed. Two and a half years later, adolescents' smoking status and nicotine dependence symptom profiles were assessed. A total of 796 adolescents were identified as smokers and included in the analyses. At follow-up, four distinct dependence symptom profiles were identified: low cravings only, high cravings and withdrawal, high cravings and behavioural dependence, and overall highly dependent. Personality traits of neuroticism and extraversion did not independently predict nicotine dependence profiles, whereas exposure to smoking in the social environment posed a risk for the initial development of nicotine dependence symptoms. However, in combination with environmental exposure to smoking, extraversion and neuroticism increased the risk of developing more severe dependence symptom profiles. Nicotine dependence profiles are predicted by interactions between personal and environmental factors. These insights offer important directions for tailoring interventions to prevent the onset and escalation of nicotine dependence. Opportunities for intervention programs that target individuals with a high risk of developing more severe dependence symptom profiles are discussed.
    BMC Public Health 03/2012; 12(1):196. DOI:10.1186/1471-2458-12-196 · 2.26 Impact Factor
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    • "The CYP2A6 genotype (the pair of specific variants, or alleles, in a gene that a person inherits, one from each parent) has been associated with the risk for being a smoker and with numerous smoking behaviors. For instance, studies in novice adolescent smokers have found that slow and normal metabolizers differ in their risk for conversion to dependence, as defined in the International Classification of Diseases, 10th Revision (ICD-10) (O’Loughlin et al., 2004) and in the rate at which they progress to increasingly severe dependence (Audrain-McGovern et al., 2007). Among adult smokers, slow metabolizers are less prevalent than intermediate or normal metabolizers; they smoke fewer cigarettes per day, exhibit reduced cigarette puffing, have decreased dependence, wait longer to smoke the first cigarette of the day, and have fewer nicotine withdrawal symptoms; and they make up a smaller portion of smokers as the duration of smoking increases, suggesting that they quit smoking sooner (Kubota et al., 2006; Malaiyandi et al., 2006; Schoedel et al., 2004; Strasser et al., 2007). "
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    ABSTRACT: Pharmacogenetics research looks at variations in the human genome and ways in which genetic factors might influence how individuals respond to drugs. The authors review basic principles of pharmacogenetics and cite findings from several gene-phenotype studies to illustrate possible associations between genetic variants, drug-related behaviors, and risk for drug dependence. Some gene variants affect responses to one drug; others, to various drugs. Pharmacogenetics can inform medication development and personalized treatment strategies; challenges lie along the pathway to its general use in clinical practice.
    Addiction science & clinical practice 12/2010; 5(2):17-29.
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