Role of CYP 2 A 6 Genet ic Variat ion on Smoking Behaviors and Cl inica l

Overview: Cigarette smoking is responsible for numerous health problems, including cancer and cardiovascular and pulmonary disorders. It is the leading cause of preventable deaths worldwide. Nicotine is primarily responsible for the highly addictive properties of cigarettes. In humans, nicotine is mainly inactivated into cotinine, and the hepatic enzyme cytochrome P450 2A6 (CYP2A6) mediates the majority of this reaction. CYP2A6 also can metabolically activate certain tobacco-specific nitrosamines into their carcinogenic forms. The gene encoding CYP2A6 is highly polymorphic, and individuals with reducedor loss-offunction alleles have significantly slower rates of nicotine metabolism. Smokers are known to regulate their nicotine intake to maintain brain and plasma levels; thus, genetic variations in CYP2A6 have been hypothesized to influence smoking behaviors. This article summarizes studies examining the role of CYP2A6 genetic variation on nicotine pharmacokinetics and smoking. Studies have associated slow CYP2A6 metabolism with an altered risk of becoming dependent, lower risk of being a smoker, lower cigarette consumption, and lower risk of lung cancer. Furthermore, this article will review how genetic variability in CYP2A6 may have clinical implications in smoking cessation. CYP2A6 activity may be a useful predictor of the efficacy of nicotine replacement therapy because it may affect the nicotine levels derived. In addition, CYP2A6 inhibitors may have utility in smoking reduction and cessation by mimicking the phenotypes of slow metabolizers.