Z-guggulsterone regulates MDR1 expression mainly through the pregnane X receptor-dependent manner in human brain microvessel endothelial cells.

Recently studies showed that pregnane X receptor (PXR) was expressed in human brain microvessel endothelial cells and coordinately induced multidrug resistance protein 1 (MDR1) expression. The present study aimed to investigate the regulatory effect of Z-guggulsterone on MDR1 in human brain microvessel endothelial cells, and explored whether it involved modulation of PXR. The results showed that Z-guggulsterone (30 μM) simultaneously inhibited the expression of PXR and MDR1 at 24 h in human brain-derived microvessel endothelial cells (hBDMECs). Meanwhile, the levels of PXR and MDR1 expression were simultaneously reduced in PXR siRNA-transfected hBDMECs; MDR-1 siRNA-transfected hBDMECs showed significant decrease in MDR1 expression, but no change in PXR expression. Furthermore, Z-guggulsterone inhibited the activation of PXR in hBDMECs through decreasing the release of cAMP/PKA. Z-guggulsterone reduced the co-activator SRC-1 expression in hBDMECs, as to prevent the activation of MDR1 gene transcription. In addition, Z-guggulsterone (30 μM) at 24 h significantly inhibited the expression of human constitutive androstane receptor (CAR) protein in hBDMECs. However, after treatment with Z-guggulsterone (≤30 μM), the level of MDR1 reporter gene activity was lower in human PXR-transfected cells than that in human CAR-transfected cells. The inhibition effect of Z-guggulsterones on MDR1 reporter gene activation was gradually enhanced with the increase of human PXR to CAR ratio, which was greater extent than that with the increase of human CAR to hPXR ratio. The present study suggested that Z-guggulsterone down-regulating the efflux function and expression of MDR1 in hBDMECs might be mainly through the PXR-dependent manner.