title: Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups.
abstract: Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P < 0.0001), and N-glucuronidation lowest in AA (P < 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.
authors.affiliation: Department of Biochemistry Molecular Biology and Biophysics and Masonic Cancer Center, University of Minnesota, 2-127 CCRB, 2231 6th Street SE, Minneapolis, MN 55455, USA, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA and Cancer Research Center of Hawai'i, University of Hawai'i, Honolulu, HI 96813, USA murph062@umn.edu.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Murphy
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA and.
authors.forename: Sung-Shim L
authors.initials: SS
authors.lastname: Park
authors.affiliation: Department of Biochemistry Molecular Biology and Biophysics and Masonic Cancer Center, University of Minnesota, 2-127 CCRB, 2231 6th Street SE, Minneapolis, MN 55455, USA, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA and Cancer Research Center of Hawai'i, University of Hawai'i, Honolulu, HI 96813, USA.
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Thompson
authors.affiliation: Cancer Research Center of Hawai'i, University of Hawai'i, Honolulu, HI 96813, USA.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA and.
authors.forename: Yesha
authors.initials: Y
authors.lastname: Patel
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA and.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.affiliation: Cancer Research Center of Hawai'i, University of Hawai'i, Honolulu, HI 96813, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
mesh_terms: D000293:Adolescent; D000328:Adult; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005838:Genotype; D005965:Glucuronates / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*
chemical_list: D005965:Glucuronates; C085795:nicotine N-glucuronide; D009538:Nicotine; C552162:UGT2B10 protein, human; D014453:Glucuronosyltransferase