P-Glycoprotein Restricts Access of Cortisol and Dexamethasone to the Glucocorticoid Receptor in Placental BeWo Cells

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Abstract

Exposure of the fetus and placenta to maternal glucocorticoids is normally limited by the placental glucocorticoid barrier, which consists primarily of placental 11 beta-hydroxysteroid 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, 11 beta-hydroxysteroid dehydrogenase type 2 and P-gp may act in unison to reduce fetal and placental exposure to maternal and thereby minimize their growth inhibitory actions.
Original languageEnglish
Pages (from-to)5147-5152
JournalEndocrinology
Volume147
Issue number11
DOIs
Publication statusPublished - 2006

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