The influence of genetically variable CYP2A6 on tobacco dependence and smoking behaviour

grantor: University of TorontoNicotine is the psychoactive substance responsible for tobacco dependence; smokers adjust their cigarette consumption to maintain central nicotine levels. In humans, 60-80% of nicotine is metabolized to cotinine by the genetically polymorphic enzyme CYP2A6, an enzyme that also bioactivates tobacco-specific procarcinogens. I postulated that individuals with impaired nicotine metabolism (carriers of CYP2A6 null alleles) would experience greater aversive effects due to higher nicotine levels, or would need to smoke fewer cigarettes. Specifically I hypothesized: (1) that there would be an under-representation of individuals carrying CYP2A6 null alleles in a tobacco-dependent population, and (2) that within dependent smokers those with deficient nicotine metabolism would smoke less. Individuals carrying CYP2A6 null alleles were less likely to become smokers as demonstrated by their decreased representation in a tobacco-dependent ($\pm$ alcohol n = 244) versus a non-dependent, but tried tobacco control (n = 184) group (12.3% versus 19.6%, P $<$ 0.04, OR = 1.74, C.I. 1.02-2.94). In addition, within the tobacco-dependent only group, those homozygous for wild-type active CYP2A6 alleles (n = 143) smoked significantly more cigarettes per day (23 vs. 19, P = 0.035) than heterozygous individuals (carriers of one null allele, n = 18). This study demonstrates that an individual with even a single CYP2A6 null allele (i.e. heterozygous) (1) has a decreased risk of becoming a dependent smoker, (2) smokes less if dependent, and (3) may be at lower risk for developing cancer due both to a decreased smoke exposure and a decreased CYP2A6-mediated bioactivation of tobacco smoke procarcinogens.M.Sc