It is well known that cigarette smoking is a prominent cause of cancers of the lung, head and neck, and other vital organs (Peto et al., 2000). In addition to its influence on nicotine metabolic inactivation, CYP2A6 also activates tobacco-specific procarcinogens, including nitrosamines, such as NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone), NDEA (N-nitrosodiethylamine), and NNN (N’-nitrosonornicotine), due to their structural similarities to nicotine. Carcinogen formation from precursor compounds is reduced in persons with reduced or null activity CYP2A6 alleles and also with CYP2A6 inhibition (Sellers et al., 2003a). Case-control studies have demonstrated that the null-activity CYP2A6*4/*4 genotype is less prevalent among lung cancer cases than healthy smoker controls, even after controlling for the impact on reducing smoking levels (Ariyoshi et al., 2002; Fujieda et al., 2004; Kamataki et al., 1999; Miyamoto et al., 1999). Thus, persons with higher levels of CYP2A6 activity (i.e., faster metabolizers of nicotine) not only are at risk for tobacco dependence and smoking persistence, but also are at increased risk for tobacco-related cancer if they smoke.
