The contribution of common UGT2B10 and CYP2A6 alleles to variation in nicotine glucuronidation among european americans

Background To develop a predictive genetic model of nicotine metabolism. UDP-glucuronosyltransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. Materials and methods The conversion of deuterated (D ²)-nicotine to D²-nicotine-glucuronide, D ²-cotinine, D²-cotinine-glucuronide, and D ²-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotineglucuronide [D²-nicotine-glucuronide/(D²-nicotine+ D ²-nicotine-glucuronide+D²-cotinine +D²- cotinineglucuronide+ D²-trans-3'-hydroxycotinine)] was the primary phenotype. Results The variant, rs61750900T (D67Y) (minor allele frequency =10%), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (minor allele frequency= 2%), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. Conclusion CYP2A6 and UGT2B10 genotype explain 53% of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with undeuterated (D⁰) nicotine glucuronidation in individuals smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. Pharmacogenetics and Genomics 23:706-716