Nicotine is primarily metabolized by a liver enzyme, cytochrome P450 2A6 (CYP2A6), which converts nicotine to cotinine (COT), and further to 3′-hydroxycotinine (3HC) [59, 60]. The ratio of 3HC/COT is a robust and highly heritable (47-67%) marker of nicotine clearance and of metabolic activity [61] and polymorphisms in the CYP2A6 gene explain 6-19% of this heritable variation [62]. There are numerous polymorphisms in CYP2A6 and their activities range from fully inactive alleles (e.g., CYP2A6*2) to those that reduce enzymatic efficiency by varying degrees (e.g., CYP2A6*9) [63]. Based on their activity, CYP2A6 alleles have been used to classify individuals into slow (homozygotes/carriers for no activity allele or carriers for reduced activity allele), intermediate (carriers for reduced activity allele) and normal metabolizers [64]. These correspond, roughly, to <50%, 50-80% and >80% CYP2A6 activity. Individuals with CYP2A6 genotypes conferring slower metabolism tend to report smoking fewer CPD, less nicotine dependence, and are more likely to quit by themselves [65, 66] (except see [67]) or with pharmacologic treatment [68] (see also [69]). However, relative to variants in other genes, including CHRNA5/CHRNA3, CYP2A6 associations less
