title: UGT1A and UGT2B genetic variation alters nicotine and nitrosamine glucuronidation in european and african american smokers.
abstract: BACKGROUND
  Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo.
  
  
  METHODS
  Within UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles.
  
  
  RESULTS
  Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P ≤ 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P = 0.008-0.04) and cotinine (P = <0.001-0.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P = 0.01, P < 0.001). UGT2B17*2 (P = 0.03) in European Americans and UGT2B7 variants (P = 0.02-0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P = 0.007-0.01), UGT2B10 (P = 0.02), and UGT2B7 (P = 0.02-0.03) variants in African Americans were nominally associated with NNAL glucuronidation.
  
  
  CONCLUSIONS
  Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation.
  
  
  CONCLUSIONS
  Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev; 24(1); 94-104. ©2014 AACR.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Wassenaar
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, California.
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois.
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois.
authors.forename: Peixian
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.affiliation: Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, Cancer Research Center, University of Chicago, Chicago, Illinois.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.affiliation: Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, University of California San Francisco, San Francisco, California. Department of Bioengineering and Therapeutic Science, University of California San Francisco, San Francisco, California.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. r.tyndale@utoronto.ca.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D014644:Genetic Variation; D060005:Genotyping Techniques; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism*; D009602:Nitrosamines / Q000378:metabolism*; D012907:Smoking / Q000235:genetics*; D044465:White People / Q000235:genetics*; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D009538:Nicotine; D009602:Nitrosamines; D000099148:UGT1A1 Enzyme; C486404:UGT2B4 protein, human