CYP2A6 metabolism in the development of smoking behaviors in young adults

Abstract

Cytochrome P450 2A6 (CYP2A6) encodes the enzyme responsible for the majority of nicotine metabolism. Previous studies support that slow metabolizers smoke fewer cigarettes once nicotine dependent but provide conflicting results on the role of CYP2A6 in the development of dependence. By focusing on the critical period of young adulthood, this study examines the relationship of CYP2A6 variation and smoking milestones. A total of 1209 European American young adults enrolled in the Collaborative Study on the Genetics of Alcoholism were genotyped for CYP2A6 variants to calculate a previously well-validated metric that estimates nicotine metabolism. This metric was not associated with the transition from never smoking to smoking initiation nor with the transition from initiation to daily smoking (P > 0.4). But among young adults who had become daily smokers (n = 506), decreased metabolism was associated with increased risk of nicotine dependence (P = 0.03) (defined as Fagerström Test for Nicotine Dependence score ≥4). This finding was replicated in the Collaborative Genetic Study of Nicotine Dependence with 335 young adult daily smokers (P = 0.02). Secondary meta-analysis indicated that slow metabolizers had a 53 percent increased odds (OR = 1.53, 95 percent CI 1.11-2.11, P = 0.009) of developing nicotine dependence compared with normal metabolizers. Furthermore, secondary analyses examining four-level response of time to first cigarette after waking (>60, 31-60, 6-30, ≤5 minutes) demonstrated a robust effect of the metabolism metric in Collaborative Study on the Genetics of Alcoholism (P = 0.03) and Collaborative Genetic Study of Nicotine Dependence (P = 0.004), illustrating the important role of this measure of dependence. These findings highlight the complex role of CYP2A6 variation across different developmental stages of smoking behaviors.

Evidence of individual differences in motives for nicotine seeking in classical nicotine self-administration and associated outcomes of varenicline administration

“…nicotine+cue self-administration behavior in our protocol relies on nicotine, the number of infusions earned over a 3hrs session was positively related to the cotinine (main nicotine metabolite) over nicotine ratio (FigS5f). Consistent with the literature (37,38) , this also supports that high nicotine intake is favored by a fast nicotine metabolism (high cotinine/nicotine ratio).…”

“…In the recent years, nicotine metabolism has focused interest as a phenotypic biomarker of smoking heaviness (37) and therapeutic response (81). Fast metabolizers being at risk for heavy smoking (37), and slow metabolizers benefitting from nicotine replacement therapies (NRT) and normal metabolizers from treatments like varenicline (81).…”

“…In the recent years, nicotine metabolism has focused interest as a phenotypic biomarker of smoking heaviness (37) and therapeutic response (81). Fast metabolizers being at risk for heavy smoking (37), and slow metabolizers benefitting from nicotine replacement therapies (NRT) and normal metabolizers from treatments like varenicline (81). Consistently, in rats, the fastest the nicotine clearance, the lowest the nicotine reinforcement threshold and the highest the degree of compensation when decreasing nicotine dose (38), and varenicline appeared more effective at reducing nicotine selfadministration in rats with a higher demand for nicotine (82).…”

Cytochrome P450 2A6 whole-gene deletion (<i>CYP2A6*4</i> ) polymorphism reduces risk of lung cancer: A meta-analysis

“…Thus, in individuals with the inactive CYP2A6 genotype, the CYP2A6 enzyme might not affect metabolic activation of N-nitrosamines and subsequently reduce the risk of lung cancer. Second, CYP2A6 is a major enzyme responsible for nicotine metabolism 38 , where inactive CYP2A6 causes lower nicotine dependence and thus affects smoking behaviour [39][40][41] .…”

Genetic variability in the neurobiology of nicotine dependence: effects on smoking behavior

“…Wassenaar et al 18 observed a higher quantity of cigarettes consumed per day by individuals possessing normal metabolizer genes in comparison with those having slow metabolizers. Although other studies have not reported the same association 74 or even divergent results 75,76 , several works have shown a direct association between the CYP2A6 genotype of lower enzyme activity and the lower risk of becoming a smoker, less nicotine dependence, fewer cigarettes consumed and greater success in cessation [17][18][19][20][21] .…”