Comparison of the modulatory effects of human and rat liver microsomal metabolism on the estrogenicity of bisphenol A: Implications for extrapolationto humans

Bisphenol A [BPA, 2,2-bis(4-hydroxyphenyl)propane], a xenoestrogen, is a mo nomer for the synthesis of polycarbonate plastics, epoxy resins, and compos ites. Metabolism of BPA to the monoglucuronide will determine the extent of its estrogenicity in vivo. Investigation of the metabolism of BPA (500 muM ) by isolated female rat hepatocytes confirmed the formation of BPA glucuro nide as the major metabolite. There was a significant difference (p < 0.05) between the V-max (mean +/- S.E.M., n = 4) of glucuronidation by pooled ma le 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 prot ein, respectively). Estrogenic activity of BPA, assessed in a coupled micro somal metabolism-yeast estrogenicity assay, was decreased 3- and 7- fold fo llowing glucuronidation by human female and immature female rat liver micro somes, respectively. Incubations of BPA with pooled human or rat liver micr osomes, in the presence of NADPH, resulted in the formation of 5-hydroxybis phenol A [2-(4,5-dihydroxyphenyl)-2-(4-hydroxyphenyl) propane], which was 1 0-fold less potent than BPA in the yeast estrogenicity assay. However, ther e was insufficient turnover to achieve a significant effect on the estrogen ic activity of BPA. Because human liver microsomes did not glucuronidate BP A as extensively as the rat liver microsomes, estrogen target tissues in hu mans may be subject to greater exposure to BPA than the tissues of the imma ture female rats used for assessing estrogenicity of xenobiotics.