Nicotine clearance involves multiple enzymatic activities converting nicotine to its various metabolites, as well as renal clearance of unaltered nicotine. A genetic model of CYP2A6 function in first-pass metabolism is an important step toward also accurately predicting individual nicotine half-life by genotype. Inclusion of further polymorphisms, especially non-coding variants not yet identified as important for CYP2A6 expression or mRNA stability, will improve the model. Another source of genetic variability affecting CYP2A6 function may be regulation of CYP2A6 expression by products of other potentially polymorphic genes [52]. Other enzymes capable of converting nicotine to cotinine in vivo, including CYP2B6, may also explain a portion of the measured variation not accounted for by CYP2A6. Variability in these other genes will play a larger role in populations with a higher frequency of CYP2A6 loss-of-function alleles than in Europeans. Ethnic differences have been demonstrated in an alternate nicotine metabolism pathway, glucuronidation [53], and genetic variation in an associated enzyme impacts smoking behavior [54]. Our successful results modeling the relationship between polymorphism in a single gene and a specific metabolism endophenotype indicate that similar investigation into other genes and parallel pathways will lead to a complete predictive genetic model of nicotine metabolism.
