P-glycoprotein restricts access of cortisol and dexamethasone to the glucocorticoid receptor in placental BeWo cells.
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.
Mark
Peter J
PJ
School of Anatomy and Human Biology, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
Waddell
Brendan J
BJ
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*
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