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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.
Acknowledgements
The authors thank Dr Chantal Guillemette (Laval University, Quebec), who provided the UGT2B15 allozymes and Dr Lauren Trepanier (University of Wisconsin, Madison, Wisconsin), who provided the breast tissue microsomes, DNA and RNA samples.
Declaration of interest
The authors report no declarations of interest.
This work was supported by the US National Institutes of Health grant GM102130 (M.H.C.), the William R. Jones endowment to Washington State University College of Veterinary Medicine (M.H.C.), the Auvil Research Fellowship (C.M.S.), and the Sigrid Juselius Foundation (M.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations.