Effect of bisphenol A on drug metabolising enzymes in rat hepatic microsomes and precision-cut rat liver slices

In order to assess the effects of bisphenol A (BPA) on enzymes of phase I and II biotransformation, studies were conducted in hepatic microsomes and precision-cut liver slices from male Sprague-Dawley rats. A testosterone hydroxylation assay was used for probing the activity of cytochrome P450 (CYP) forms, and an appropriate HPLC method for the separation of testosterone metabolites was developed. BPA markedly inhibited the hydroxylation of testosterone at 2alpha and 16alpha but not at 6beta or 7alpha, suggesting a differential inhibition of some CYP forms, in particular CYP2C11. This inhibitory effect was also observed when slices were first exposed to BPA and then incubated with testosterone in the absence of BPA, indicative of an irreversible inhibition of CYP. In liver slices, a differential conjugation of hydroxylated testosterone metabolites was observed, which was significantly decreased in the presence of BPA. BPA also inhibited the conjugation of the model compound umbelliferone. Pretreatment with BPA did not affect the conjugation of testosterone and umbelliferone. No hydroxylation, but extensive conjugation of BPA was observed upon incubation of liver slices with BPA alone or with testosterone or umbelliferone. The rapid and preferred conjugation, however, does not prevent the irreversible inhibition of some CYP forms by BPA. In conclusion, this study has shown that BPA causes a selective and irreversible inhibition of certain CYP forms and interferes with the conjugation of other drugs.