Effect of bisphenol A on drug efflux in BeWo, a human trophoblast-like cell line.
Bisphenol A (BPA) is a monomer of polycarbonate plastics that has estrogenic activities and has been shown to be a substrate for multidrug resistant efflux mechanisms, specifically, P-glycoprotein. Since the natural hormone estrogen reverses multidrug resistance in some cell types, we hypothesized that BPA might have a similar activity in trophoblasts. We have used BeWo cells as an in vitro model for human trophoblasts and calcein AM as a substrate for drug efflux mechanism to characterize BPA interactions with placental P-glycoprotein. We found that chronic exposure of BeWo cells to BPA did not alter intracellular calcein accumulation in a fashion that would be reflective of changes in P-glycoprotein expression. Immunoblots affirmed that BPA had small effects on P-glycoprotein expression. However, BeWo cells acutely exposed to BPA pretreatment were observed to have a significantly decreased calcein accumulation. Addition of cyclosporin A, a P-glycoprotein inhibitor and substrate, completely reversed BPA's effects on calcein accumulation and resulted in a net increase, relative to controls, in calcein accumulation by the BeWo cells. BPA was found not to stimulate P-gp ATPase or alter intracellular esterases mediating calcein release from calcein AM. Therefore, our results suggested that BPA stimulated drug efflux by BeWo cells probably by direct effects on P-glycoprotein.
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Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001559:Benzhydryl Compounds; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004950:Esterases / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005260:Female; D005452:Fluoresceins / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D010636:Phenols / Q000633:toxicity*; D011247:Pregnancy; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism*; D000098826:Bisphenol A Compounds
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases; D001559:Benzhydryl Compounds; D016572:Cyclosporine; D004950:Esterases; D004958:Estradiol; D004968:Estrogens, Non-Steroidal; D005452:Fluoresceins; D005456:Fluorescent Dyes; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C007740:fluorexon