title: The influence of genetic polymorphisms in Ahr, CYP1A1, CYP1A2, CYP1B1, GST M1, GST T1 and UGT1A1 on urine 1-hydroxypyrene glucuronide concentrations in healthy subjects from Rio Grande do Sul, Brazil.
abstract: Polymorphisms in genes encoding polycyclic aromatic hydrocarbon (PAH) metabolizing enzymes may alter metabolism of these carcinogens and contribute to inter-individual difference in urine concentrations. We investigated the influence of genetic polymorphism on PAH metabolism in urine from 199 healthy subjects from Southern Brazil. We measured urine 1-hydroxypyrene glucuronide (1-OHPG) concentrations using immunoaffinity chromatography and synchronous fluorescence spectroscopy and genotyped subjects using standard methods. Genetic variants in CYP1B1 (rs1056827, rs1800440, rs10012) were strongly associated with urine 1-OHPG with P-values < 0.010. Variants in aryl hydrocarbon receptor (Ahr) (rs4986826), CYP1A1 (rs1799814) and CYP1A2 (rs2069514) were also, although less strongly, associated with changes in urine 1-OHPG concentrations. These variants had P-values of 0.074, 0.040 and 0.025, respectively. The median urine 1-OHPG concentrations (pmol/ml) in the homozygous wild-type and homozygous variants for CYP1B1 (rs10012) and the Ahr, CYP1A1 and CYP1A2 variants listed above were 2.16 and 0.10, 2.16 and 0.41, 2.03 and 0.46, 2.19 and 2.79, respectively. We found no effect of deletions in GST M1 or GST T1, or different alleles of UGT1A1*28. Adjusting for age, sex, place of residence, tobacco smoke exposure, maté drinking, cachaça and barbeque preparation had only a minor impact on the associations. A model containing just exposure variables had an r2 of 0.21; a model with single genotypes for Ahr, CYP1A1, CYP1A2 and CYP1B1 had an r2 of 0.10; and a model combining both exposure and genotype information had a total r2 of 0.33. Our results suggest that CYP1B1 genotypes are strongly associated with urine 1-OHPG concentrations in this population.
authors.affiliation: Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, EPS/320, MSC 7232, Rockville, MD 20852, USA. abnetc@mail.nih.gov
authors.forename: Christian C
authors.initials: CC
authors.lastname: Abnet
authors.forename: Renato B
authors.initials: RB
authors.lastname: Fagundes
authors.forename: Paul T
authors.initials: PT
authors.lastname: Strickland
authors.forename: Farin
authors.initials: F
authors.lastname: Kamangar
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Roth
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Sanford M
authors.initials: SM
authors.lastname: Dawsey
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001938:Brazil / Q000453:epidemiology; D002846:Chromatography, Affinity; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D005260:Female; D005965:Glucuronates / Q000652:urine*; D014453:Glucuronosyltransferase / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011721:Pyrenes; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D000099148:UGT1A1 Enzyme
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D005965:Glucuronates; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D011721:Pyrenes; D018336:Receptors, Aryl Hydrocarbon; D000099148:UGT1A1 Enzyme; C093851:1-hydroxypyrene-glucuronide; C585496:CYP1B1 protein, human; C413545:glutathione S-transferase T1