title: The contribution of common UGT2B10 and CYP2A6 alleles to variation in nicotine glucuronidation among European Americans.
abstract: BACKGROUND
  To develop a predictive genetic model of nicotine metabolism. UDP-glucuronosyltransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation.
  
  
  METHODS
  The conversion of deuterated (D2)-nicotine to D2-nicotine-glucuronide, D2-cotinine, D2-cotinine-glucuronide, and D2-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 nicotine-glucuronide [D2-nicotine-glucuronide/(D2-nicotine+D2-nicotine-glucuronide+D2-cotinine+D2-cotinine-glucuronide+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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: aDepartment of Psychiatry, Washington University School of Medicine, St Louis, Missouri bDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: A Joseph
authors.initials: AJ
authors.lastname: Bloom
authors.forename: Linda B
authors.initials: LB
authors.lastname: von Weymarn
authors.forename: Maribel
authors.initials: M
authors.lastname: Martinez
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009538:Nicotine / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics; D014481:United States; D044465:White People / Q000235:genetics*
chemical_list: D020719:Glucuronides; D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C552162:UGT2B10 protein, human; D014453:Glucuronosyltransferase