title: P-glycoprotein restricts access of cortisol and dexamethasone to the glucocorticoid receptor in placental BeWo cells.
abstract: Exposure of the fetus and placenta to maternal glucocorticoids is normally limited by the placental glucocorticoid barrier, which consists primarily of placental 11beta-hydroxy-steroid dehydrogenase type 2-mediated conversion of cortisol to the biologically inactive cortisone. Studies in the rodent brain show that P-glycoprotein (P-gp) is also an important physiological regulator of glucocorticoid access to the glucocorticoid receptor (GR) in target cells because it exports cortisol back into peripheral circulation against a concentration gradient. Whether P-gp of placental origin also has this capacity is unknown. Therefore, we used the human placental choriocarcinoma cell line BeWo and its daughter cell line, BeWoMDR, virally transduced with P-gp, to assess whether placental P-gp regulates access of glucocorticoids to the GR. Quantitative PCR showed that BeWoMDR cells express approximately 10-fold higher levels of P-gp mRNA than BeWo cells, and syncytialization increased P-gp mRNA by approximately 7-fold. Elevated P-gp expression in BeWoMDR cells reduced activation of the GR by dexamethasone and cortisol (10(-9) to 10(-6) M) to around 40% of that in BeWo cells. Inhibition of P-gp-mediated glucocorticoid efflux by cyclosporin A in BeWoMDR cells returned GR activation to levels similar to those in BeWo cells. Diffusion of dexamethasone across BeWoMDR monolayers occurred at a slower rate than that across BeWo monolayers, but this difference was eliminated by cyclosporin A. These data support the hypothesis that P-gp contributes to the placental glucocorticoid barrier. Thus, 11beta-hydroxysteroid dehydrogenase type 2 and P-gp may act in unison to reduce fetal and placental exposure to maternal glucocorticoids and thereby minimize their growth inhibitory actions.
authors.affiliation: School of Anatomy and Human Biology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mark
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Waddell
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000502:physiology; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000378:metabolism / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000493:pharmacokinetics / Q000494:pharmacology*; D015735:Mifepristone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000187:drug effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D016572:Cyclosporine; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006854:Hydrocortisone