Department of Scientific Research, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Clinical Pharmacy, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
Eur J Pharmacol. 2020 May 5;874:173023. doi: 10.1016/j.ejphar.2020.173023. Epub 2020 Feb 19.
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.
最近的研究表明，孕烷 X 受体 (PXR) 存在于人脑微血管内皮细胞中，并协同诱导多药耐药蛋白 1 (MDR1) 的表达。本研究旨在探讨 Z- 古卡斯特酮对人脑微血管内皮细胞中 MDR1 的调节作用，并探讨其是否涉及 PXR 的调节。结果表明，Z- 古卡斯特酮 (30 μM) 可同时抑制人源性脑微血管内皮细胞 (hBDMECs) 中 PXR 和 MDR1 的表达，在 PXR siRNA 转染的 hBDMECs 中同时降低 PXR 和 MDR1 的表达；MDR-1 siRNA 转染的 hBDMECs 中 MDR1 表达明显降低，但 PXR 表达无变化。此外，Z- 古卡斯特酮通过降低 cAMP/PKA 的释放，抑制 PXR 在 hBDMECs 中的激活。Z- 古卡斯特酮降低了 hBDMECs 中的共激活因子 SRC-1 表达，从而防止 MDR1 基因转录的激活。此外，Z- 古卡斯特酮 (30 μM) 在 24 h 时显著抑制 hBDMECs 中人组成型雄烷受体 (CAR) 蛋白的表达。然而，用 Z- 古卡斯特酮处理后 (≤30 μM)，人 PXR 转染细胞中的 MDR1 报告基因活性低于人 CAR 转染细胞。Z- 古卡斯特酮对 MDR1 报告基因激活的抑制作用随人 PXR 与 CAR 比值的增加而逐渐增强，其程度大于人 CAR 与 hPXR 比值的增加。本研究表明，Z- 古卡斯特酮下调 hBDMECs 中 MDR1 的外排功能和表达可能主要通过 PXR 依赖性途径。
