Differential regulation of intestinal efflux transporters by pregnancy in mice

Abstract

1. In the intestines, the nuclear receptors farnesoid X receptor (Fxr) and pregnane X receptor (Pxr) regulate the transcription of metabolizing enzymes and transporters that dictate the absorption of nutrients and xenobiotics.2. Here, we sought to determine whether Fxr and Pxr signaling pathways are disrupted in response to high-circulating concentrations of steroid hormones late in pregnancy leading to altered transporter expression. To test this, ileum were collected from virgin and pregnant C57BL/6 mice on gestation days 14, 17 and 19.3. Ileum from pregnant mice exhibited suppression of Fgf15 and Cyp3a11 mRNAs, which are the prototypical target genes for Fxr and Pxr, respectively. An overall reduction in the expression of apical efflux transporters, including Mdr1, Mrp2 and Bcrp, was observed in pregnant mice. To assess the ability of steroid hormones to alter intestinal nuclear receptor signaling, transporter mRNA expression was quantified in human intestinal LS174T adenocarcinoma cells. In vitro data demonstrated that progestins reduced CYP3A4, MDR1 and MRP2 mRNA expression by 30–40%.4. These data suggest that progesterone may act as a mediator to negatively regulate efflux transporter expression in the mouse ileum during pregnancy possibly by reducing PXR/Pxr signaling. This may affect drug absorption and disposition during pregnancy.