Several possible reasons exist for the discrepant results, including differing phenotypic definitions of addiction across studies, different genotypic markers of metabolism, and different measures of addiction (18). The majority of studies of adolescent nicotine metabolism focused on polymorphisms of the CYP2A6 gene, which, when present, are associated with slower nicotine metabolism (13, 14, 19). A limitation of using genotypic markers for metabolic rate is that nicotine metabolism is affected differently by the many functionally significant polymorphisms of the CYP2A6 gene (20). Moreover, nicotine metabolism can be affected by other factors, including other genes (e.g., CYP2B6 and CYP2E1) and environmental factors, such as medications (e.g., oral contraceptives) (21, 22). Thus, even smokers with wild type CYP2A6genes, who are nominally normal metabolizers, demonstrate more than four-fold variability in the rate of nicotine metabolism (9). Measurement of the rate of nicotine metabolism using phenotypic measures rather than genetic markers will capture the integrated contribution from these other influences (23, 24).
