The genetic aspects of nicotine metabolism and their impact on adolescent nicotine dependence

Abstract

In humans, nicotine is extensively metabolized via multiple pathways that are catalyzed by genetically variable enzymes. As a result, there is large interindividual and interethnic variability observed in nicotine pharmacokinetics. Twin studies suggest an important role for genetic factors, although environmental and physiological factors also contribute to this variability. The present chapter focuses on the genetics of nicotine metabolism and its impact on smoking behaviors with specific emphasis on the adolescent period. Enzymes involved in nicotine metabolism include cytochromes P450 (CYPs), aldehyde oxidase (AOX1), UDP-Glucuronosyltransferases (UGTs), and flavin-containing monooxygenase 3 (FMO3). CYP2A6 is the main enzyme involved in nicotine's metabolic inactivation; CYP2A6 genetic variants contribute substantially to the observed variability in nicotine metabolism. In addition, genetic variation in CYP2A6 has been associated with multiple smoking behaviors in adults (e.g. risk of smoking, level of cigarette consumption, depth of inhalation, and ability to stop smoking). Among adolescents, two longitudinal cohort studies showed a consistent effect of CYP2A6 genetic variation on level of smoking among dependent adolescents but found different effects with respect to the association of CYP2A6 with onset versus progression of nicotine dependence. We re-examined these two studies in detail in order to more fully understand these findings. Understanding variability in nicotine metabolism assists in understanding variability in response to nicotine and liability to smoking, providing the potential of identifying individuals at greater risk for smoking, sustained smoking and smoking related disorders and also may assist in personalizing treatment to improve efficacy of nicotine replacement therapies.

Keywords

CYP2A6 - nicotine - pharmacogenetics - adolescent - smoking