Nicotine is the major substance in tobacco responsible for addiction among cigarette smokers (62). An in vivo study has shown that approximately 80% of nicotine consumed is metabolically inactivated to cotinine (12); approximately 90% of this conversion is mediated by CYP2A6 (92, 99). The next step of nicotine metabolism, which oxidizes cotinine to form trans-3′-hydroxycotinine, is entirely catalyzed by CYP2A6 (98). CYP2A6 is a highly polymorphic enzyme. Different CYP2A6 alleles have different functional consequences, and the frequency of CYP2A6 alleles varies among ethnic populations (97). A number of studies have reported association between reduced or absent CYP2A6 enzyme activity and lower risk of smoking, including decreased cigarette consumption, smoking intensity, and withdrawal symptoms; shorter smoking duration; and increased cessation. However, some studies have failed to detect any association between CYP2A6 variation and smoking status (64). A recent study using quantified measures of deuterated (D2)-cotinine/(D2-cotinine + D2-nicotine) following oral administration in 189 European Americans demonstrated that CYP2A6*12 is a loss-of-function allele indistinguishable from CYP2A6*4 and CYP2A6*2 alleles, and that the CYP2A6*1B 5′ untranslated region conversion has a negligible impact on metabolism
