Glucocorticoids modulate multidrug resistance transporters in the first trimester human placenta

Abstract

The placental multidrug transporters, P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP, ABCG2) protect the foetus from exposure to maternally derived glucocorticoids, toxins and xenobiotics. During pregnancy, maternal glucocorticoid levels can be elevated by stress or exogenous administration. We hypothesized that glucocorticoids modulate the expression of ABCB1/P-gp and ABCG2/BCRP in the first trimester human placenta. Our objective was to examine whether dexamethasone (DEX) or cortisol modulate first trimester placental expression of multidrug transporters and determine whether cytotrophoblasts or the syncytiotrophoblast are/is responsible for mediating these effects. Three models were examined: (i) an ex-vivo model of placental villous explants (7-10 weeks), (ii) a model of isolated first trimester syncytiotrophoblast and cytotrophoblast cells and (iii) the BeWo immortalized trophoblast cell line model. These cells/tissues were treated with DEX or cortisol for 24 hour to 72 hour. In first trimester placental explants, DEX (48 hour) increased ABCB1 (P < .001) and ABCG2 (P < .05) mRNA levels, whereas cortisol (48 hour) only increased ABCB1 mRNA levels (P < .01). Dexamethasone (P < .05) and cortisol (P < .01) increased BCRP but did not affect P-gp protein levels. Breast cancer resistance protein expression was primarily confined to syncytiotrophoblasts. BeWo cells, when syncytialized with forskolin, increased expression of BCRP protein, and this was further augmented by DEX (P < .05). Our data suggest that the protective barrier provided by BCRP increases as cytotrophoblasts fuse to form the syncytiotrophoblast. Increase in glucocorticoid levels during the first trimester may reduce embryo/foetal exposure to clinically relevant BCRP substrates, because of an increase in placental BCRP.

Keywords: BeWo; P-glycoprotein (P-gp); breast cancer related protein (BCRP); dexamethasone; first trimester placenta; glucocorticoids.