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Vol. 297, Issue 1, 103-113, April 2001

Comparison of the Modulatory Effects of Human and Rat Liver Microsomal Metabolism on the Estrogenicity of Bisphenol A: Implications for Extrapolation to Humans

Robert Elsby, James L. Maggs, John Ashby and B. Kevin Park

Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom (R.E., J.L.M., B.K.P.); and Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom (J.A.)

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.

0022-3565/01/2971-0103$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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