title: Bisphenol-A glucuronidation in human liver and breast: identification of UDP-glucuronosyltransferases (UGTs) and influence of genetic polymorphisms.
abstract: 1. Bisphenol-A is a ubiquitous environmental contaminant that is primarily metabolized by glucuronidation and associated with various human diseases including breast cancer. Here we identified UDP-glucuronosyltransferases (UGTs) and genetic polymorphisms responsible for interindividual variability in bisphenol-A glucuronidation in human liver and breast. 2. Hepatic UGTs showing the highest bisphenol-A glucuronidation activity included UGT2B15 and UGT1A9. Relative activity factor normalization indicated that UGT2B15 contributes >80% of activity at bisphenol-A concentrations under 5 μM, while UGT1A9 contributes up to 50% of activity at higher concentrations. 3. Bisphenol-A glucuronidation by liver microsomes (46 donors) ranged from 0.25 to 4.3 nmoles/min/mg protein. Two-fold higher glucuronidation (p = 0.018) was observed in UGT1A9 *22/*22 livers compared with *1/*1 and *1/*22 livers. However, no associations were observed for UGT2B15*2 or UGT1A1*28 genotypes. 4. Bisphenol-A glucuronidation by breast microsomes (15 donors) ranged from <0.2 to 56 fmoles/min/mg protein. Breast mRNA expression of UGTs capable of glucuronidating bisphenol-A was highest for UGT1A1, followed by UGT2B4, UGT1A9, UGT1A10, UGT2B7 and UGT2B15. Bisphenol-A glucuronidation was over 10-fold lower in breast tissues with the UGT1A1*28 allele compared with tissues without this allele (p = 0.006). 5. UGT2B15 and UGT1A9 contribute to glucuronidation variability in liver, while UGT1A1 is important in breast.
authors.affiliation: a Department of Veterinary Clinical Sciences , Pharmacogenomics Laboratory, Program in Individualized Medicine (PrIMe), College of Veterinary Medicine, Washington State University , Pullman , WA , USA and.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Street
authors.affiliation: a Department of Veterinary Clinical Sciences , Pharmacogenomics Laboratory, Program in Individualized Medicine (PrIMe), College of Veterinary Medicine, Washington State University , Pullman , WA , USA and.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: b Division of Pharmaceutical Chemistry and Technology , Faculty of Pharmacy, University of Helsinki , Helsinki , Finland.
authors.forename: Moshe
authors.initials: M
authors.lastname: Finel
authors.affiliation: a Department of Veterinary Clinical Sciences , Pharmacogenomics Laboratory, Program in Individualized Medicine (PrIMe), College of Veterinary Medicine, Washington State University , Pullman , WA , USA and.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Court
mesh_terms: D001559:Benzhydryl Compounds / Q000378:metabolism*; D001940:Breast / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D015386:Hazardous Substances / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D010636:Phenols / Q000378:metabolism*; D011110:Polymorphism, Genetic; D000099148:UGT1A1 Enzyme; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D014453:Glucuronosyltransferase; D015386:Hazardous Substances; D010636:Phenols; D000099148:UGT1A1 Enzyme; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Bisphenol-A; breast; breast cancer; glucuronidation; liver