Glucuronidation of Nicotine and Cotinine by UGT2B10: Loss of Function by the UGT2B10 Codon 67 (Asp>Tyr) Polymorphism

摘要: Nicotine, the major addicting agent in tobacco and smoke, undergoes a complex metabolic pathway, with ∼22% of nicotine urinary metabolites form phase II N -glucuronidated compounds. Recent studies have shown that UGT2B10 is enzyme involved -glucuronidation several tobacco-specific nitrosamines. In present study, microsomes UGT2B10-overexpressing HEK293 cells exhibited high activity against both cotinine apparent K M 9s were 37- 3-fold lower than observed for UGT1A4-overexpressing cotinine, respectively. The from wild-type (WT) was similar to human liver (HLM) substrates. level glucuronidated or 112 HLM samples correlated genotype; levels nicotine- cotinine-glucuronide 21% 30% specimens subjects (*1/*2) genotype compared WT (*1/*1) 5- 16-fold formation, respectively, (*2/*2) genotype. contrast relatively overexpressing vitro , little no glucuronidation UGT2B10*2 variant either cotinine. These data suggest hepatic nicotine/cotinine significantly reduces cotinine- formation plays an important role metabolism elimination. [Cancer Res 2007;67(19):9024–9]