Vitamin D receptor regulate placental ABCB1 expression transcriptionally by recruiting coactivator SRC-1.

Abstract

Background: P-glycoprotein (P-gp), the most extensively studied ATP-binding cassette (ABC) transporter, is expressed in the apical membrane of syncytiotrophoblast cells and plays a crucial role in placental drug transport. However, the roles of the vitamin D receptor (VDR) and steroid receptor coactivators (SRCs) family members in VDR-mediated transcriptional regulation of the ABCB1 gene in response to 1,25-dihydroxyvitamin D3 in the placenta remain unclear.

Methods: VDR-mediated drug efflux was first examined using VDR-deficient mice. Subsequently, the roles of VDR and SRCs in regulating placental P-gp were investigated via specific deletion of VDR and SRCs in mouse trophoblast cells in vivo, and further validated using transfection assays in placental trophoblast cells in vitro. Additionally, the mechanisms underlying VDR-regulated ABCB1 expression were explored.

Results: In this study, we first knocked out the Vdr gene in C57BL/6J mice and observed a significant downregulation of P-gp in the placenta. Furthermore, both gain-of-function and loss-of-function assays demonstrated that VDR promotes P-gp expression in human trophoblast cells. Mechanistically, VDR induces ABCB1 gene transcription by binding to the region 2026-2031 bp upstream of the transcriptional start site in the ABCB1 gene promoter in human trophoblast cells. Moreover, we found that SRCs interact with VDR in trophoblast cell lines, and both in vivo and in vitro studies showed that SRC-1 enhances placental ABCB1 expression. Further investigations confirmed that SRC-1 is an essential transcriptional coactivator for VDR-mediated ABCB1 transactivation in human trophoblast cells.

Conclusions: Our findings reveal a novel mechanism regulating placental P-gp expression, which may assist clinicians in ensuring the safety of drug therapy during pregnancy.