Nicotine Psychopharmacology

Volume 192 of the series Handbook of Experimental Pharmacology pp 235-259

Molecular Genetics of Nicotine Metabolism

  • Jill C. MwenifumboAffiliated withCentre for Addiction & Mental Health and Department of Pharmacology, University of Toronto
  • , Rachel F. TyndaleAffiliated withCenter for Addiction and Mental Health and Department of Pharmacology, University of Toronto

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The molecular genetics of nicotine metabolism involves multiple polymorphic catalytic enzymes. Variation in metabolic pathways results in nicotine disposition kinetics that differ between individuals and ethnic groups. Twin studies indicate that a large part of this variance is genetic in origin, although environmental influences also contribute. The primary aim of this chapter is to review the current knowledge regarding the genetic variability in the enzymes that metabolize nicotine in humans. The focus is on describing the genetic polymorphisms that exist in cytochromes P450 (CYPs), aldehyde oxidase 1 (AOX1), UDP-glucuronosyltransferases (UGTs), and flavin-containing monooxygenase 3 (FMO3). Genetic studies have demonstrated that polymorphisms in CYP2A6, the primary enzyme responsible for nicotine breakdown, make a sizable contribution to the wide range of nicotine metabolic capacity observed in humans. Thus, special attention will be given to CYP2A6, because slower nicotine metabolism requires less frequent self-administration, and accordingly influences smoking behaviors. In addition, the molecular genetics of nicotine metabolism in nonhuman primates, mice, and rats will be reviewed briefly.