Gene–gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism

• DOI: 10.1097/01.fpc.0000220560.59972.33
• Publication Date: 2008-05-04T12:40:43Z
• Authors: Huijun Z. Ring; Ana M. Valdes; Denise M. Nishita; Suman Prasad; Peyton Jacob; Rachel F. Tyndale; Gary E. Swan; Neal L. Benowitz
• Keywords: CYP2A6; Cotinine; CYP2B6

CYP2A6 is the major enzyme involved in nicotine metabolism, yet large interindividual variations rate of metabolism exist within groups individuals having same genotype. We investigated influence genetic variation another potential nicotine-metabolizing enzyme, CYP2B6, and its interaction with CYP2A6, on nicotine.Two hundred twelve healthy Caucasian adult twin volunteers underwent an intravenous infusion stable isotope-labeled metabolite, cotinine, for characterization pharmacokinetic phenotypes. Five CYP2B6 polymorphisms causing amino acid substitutions (R22C, Q172 H, S259R, K262R, R487C) were analyzed.We observed that CYP2B6*6 haplotype (defined as both H K262R variants) was associated faster cotinine clearance, such associations more prominent among decreased-activity genotypes. Statistically significant interactions between genotypes (P<0.003 clearance P<0.002 clearance).Our results indicate decreased activity. Further investigation roles mediating dependence tobacco-related diseases merited.