Comparison of the Modulatory Effects of Human and Rat Liver Microsomal Metabolism on the Estrogenicity of Bisphenol A: Implications for Extrapolation to Humans
- 1Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom (R.E., J.L.M., B.K.P.); and 2Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.A.)
Abstract
Bisphenol A [BPA, 2,2-bis(4-hydroxyphenyl)propane], a xenoestrogen, is a monomer for the synthesis of polycarbonate plastics, epoxy resins, and composites. Metabolism of BPA to the monoglucuronide will determine the extent of its estrogenicity in vivo. Investigation of the metabolism of BPA (500 μM) by isolated female rat hepatocytes confirmed the formation of BPA glucuronide as the major metabolite. There was a significant difference (p < 0.05) between the Vmax (mean ± S.E.M.,n = 4) of glucuronidation by pooled male or female human (four livers in each case) and immature female rat liver microsomes (5.9 ± 0.4, 5.2 ± 0.3, and 31.6 ± 8.1 nmol/min/mg of protein, respectively). Estrogenic activity of BPA, assessed in a coupled microsomal metabolism-yeast estrogenicity assay, was decreased 3- and 7-fold following glucuronidation by human female and immature female rat liver microsomes, respectively. Incubations of BPA with pooled human or rat liver microsomes, in the presence of NADPH, resulted in the formation of 5-hydroxybisphenol A [2-(4,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)propane], which was 10-fold less potent than BPA in the yeast estrogenicity assay. However, there was insufficient turnover to achieve a significant effect on the estrogenic activity of BPA. Because human liver microsomes did not glucuronidate BPA as extensively as the rat liver microsomes, estrogen target tissues in humans may be subject to greater exposure to BPA than the tissues of the immature female rats used for assessing estrogenicity of xenobiotics.
Footnotes
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Send reprint requests to: Professor B. K. Park, Department of Pharmacology and Therapeutics, University of Liverpool, New Medical Bldg., Ashton St., Liverpool, L69 3BX UK. E-mail:bkpark{at}liverpool.ac.uk
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This work was supported by a collaborative studentship between the Medical Research Council and Zeneca Central Toxicology Laboratory (to R.E.). B.K.P. is a Wellcome Principal Fellow. The LC-MS system was purchased and maintained with grants from the Wellcome Trust.
- Abbreviations:
- BPA
- bisphenol A
- E2
- 17β-estradiol
- ER
- estrogen receptor
- 5-OHBPA
- 5-hydroxybisphenol A
- UGT
- UDP-glucuronosyltransferase
- UDPGA
- uridine diphosphate glucuronic acid
- bis-OH-MXC
- bis-hydroxy-methoxychlor
- HPLC
- high performance liquid chromatography
- LC-MS
- liquid chromatography mass spectrometry
- SIM
- selected-ion monitoring
- Rt
- retention time
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- Received October 27, 2000.
- Accepted December 13, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
