Glucuronidation of nicotine and cotinine by UGT2B10: Loss of function by the UGT2B10 codon 67 (Asp>Tyr) polymorphism

Gang Chen, Andrea S. Blevins-Primeau, Ryan W. Dellinger, Joshua E. Muscat, Philip Lazarus

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)9024-9029
Number of pages6
JournalCancer Research
Volume67
Issue number19
DOIs
StatePublished - Oct 1 2007

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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