It has been demonstrated that smokers titrate levels of smoking in order to maintain a particular level of nicotine in their system, and manipulation of the rates of nicotine clearance alter smoking behaviors (reviewed in (43)). As such, variability in CYP2A6, the main metabolic inactivating enzyme for nicotine (Fig. 1), can influence smoking behaviors, dependence and cessation. There are currently 38 CYP2A6 alleles identified (including SNPs, gene conversions, deletions and duplications, http://www.cypalleles.ki.se/cyp2a6.htm), and much progress has been made to understand their functional impact. Many of these genetic variants significantly alter the rate of nicotine metabolism among a variety of populations (reviewed in (43), Supplementary Table 1). Consistent with this, many studies (of primarily heavy-smoking Caucasians or Japanese ethnicity) have shown that smokers with genetic variants that impair CYP2A6 function, reducing nicotine metabolism, smoke fewer cigarettes, are less likely to be adult current smokers, and have a lower risk of lung cancer (reviewed in (4, 43), Supplementary Table 1, 3). Some studies have also indicated that reduced CYP2A6 activity may also alter the rate of acquisition of nicotine dependence and the rate of the escalation of dependence (48, 49).
