Affiliations: Centre for Addiction and Mental Health, Department of
Pharmacology and Toxicology, Department of Psychiatry, University of Toronto, Toronto, Canada | Department of Social and Preventive Medicine,
University of Montreal, CR-CHUM, Institute National de Sante Publique du
Quebec, Canada | Department of Psychiatry, University of Pennsylvania,
Philadelphia, PA, USA
Note: [] Correspondence: Rachel F. Tyndale, 1 King's College Circle,
University of Toronto, Medical Sciences Building, Room 4326, Toronto, Ontario,
Canada, M5S 1A8, Tel.: +1 416 978 6374; Fax: +1 416 978 6395; E-mail: [email protected]
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.
