สนทนาIn this longitudinal study in adolescent smokers, we extendprevious findings of an increased riskfor tobacco dependence acquisition among CYP2A6 slow nicotinemetabolizers relative to CYP2A6 normal metabolizers, by demonstrating that this elevated risk occurs throughout adolescence.Despite their increased risk of acquisition, CYP2A6 slow metabolizers are also more likely to quit smoking throughout adolescenceand adulthood; thusdepending on the point in time during the transition from adolescence to adulthood, or in smoking dependence trajectory, slowmetabolizers may be over or underrepresented in smokers versusnon-smokers. This may contribute to the observed lower riskamong slow (vs. normal) metabolizers for being a smoker versusnon-smoker in young adulthood. Whilethe precise mechanism(s) underlying the association between CYP2A6 slow metabolism and increased risk for tobacco depend-ence acquisition in adolescence is unknown, our data suggestthat experiencing early nausea or dizziness may not contribute.The effect of slower nicotine metabolism on nicotine-mediatedreward was recently characterized in nicotine-naïve adult mice. Slower nicotine metabolism, achieved throughmethoxsalen-mediated inhibition of CYP2A5 (the murine orthologof human CYP2A6), caused animals to display a preference fornicotine in the conditioned place preference paradigm, suggestive of greater reward. Ifthese findings extend to novice smokers, those with slow nico-tine metabolism may also experience greater reward during initialsmoking experiences, potentially due to greater nicotine exposure,increasing their risk for developing nicotine dependence.Despite their higher risk of acquiring tobacco dependence, oncedependent, the level of cigarette consumption appeared to belower in CYP2A6 slow (vs. normal) metabolizers, however this wasnot significant. Slow nicotine metabolism, measured by CYP2A6 genotype or NMR, is associated with lower cigarette consumptionamong dependent adults smoking a mean of 18+ cigarettes/day. Future investigations will clarify whether dependent adolescent smokers, even at comparatively lower levels of cigaretteconsumption versus adults, titrate their level of nicotine intakeaccording to their rate of nicotine metabolism in order to main-tain desirable levels,with CYP2A6 slow metabolizers needing to smoke fewercigarettes to achieve these levels. In contrast to CYP2A6, variationin CYP2B6 does not substantially alter the rate of peripheral nico-tine metabolism or cigarette consumption (Lee et al., 2007b); wealso showed a lack of significant association between CYP2B6 andadolescent cigarette consumption.In a cross-sectional study of adolescent smokers (<5 cigarettes/day) aged 13 to 17 years (mean = 16 years), NMR was negatively associated with mFTQ dependence scores and cigarette consumption, where slower metabolizers displayed both higher dependenceand higher consumption. It is possible thatthis study captured an earlier time-point in smoking history thanour study, where the CYP2A6 slow metabolizers were more likelyto be dependent (and have higher dependence scores), but hadnot yet begun to titrate their nicotine intake according to theirrate of nicotine metabolism (i.e., had not begun to smoke fewercigarettes).
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