Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells
Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells
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DOI：
10.1111/j.1471-4159.2011.07288.x
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发表时间：
2011-07-01
影响因子：
4.7
通讯作者：
Bendayan, Reina
中科院分区：
文献类型：
--
作者：
Chan, Gary N. Y.;Hoque, Tozammel;Bendayan, Reina
在哺乳动物系统中，孕烷X受体（PXR）和组成型雄烷受体（CAR）被认为是外源传感器，可以上调p-糖蛋白（P-gp）等药物转运蛋白的功能表达。在大脑中，P-gp表达的增加可以进一步限制药物通过血脑屏障（BBB）的通透性，并可能降低中枢神经系统药物治疗的疗效。目前，人类PXR （hPXR）和CAR （hCAR）是否参与了人类血脑屏障P-gp表达的调控尚不清楚。在这项研究中，我们利用人脑微血管内皮细胞培养系统研究了hPXR和hCAR在P-gp表达调控中的作用。我们证明，通过各自的配体激活hPXR和hCAR可在mRNA和蛋白质水平上诱导P-gp，而hPXR和hCAR的药物抑制剂可阻止配体介导的P-gp诱导。观察到配体诱导的hPXR核易位，尽管这种效应在hCAR中无法证明。此外，使用小干扰RNA下调hPXR和hCAR蛋白可降低P-gp的表达。我们的发现提供了hPXR和hCAR在人类血脑屏障中调控P-gp的第一个证据，并为如何在该位点实现选择性P-gp调控提供了见解。
In mammalian systems, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been recognized as xenobiotic-sensors which can up-regulate the functional expression of drug transporters, such as P-glycoprotein (P-gp). In the brain, an increase in P-gp expression can further limit drug permeability across the blood-brain barrier (BBB) and potentially reduce CNS pharmacotherapy efficacy. At present, the involvement of human PXR (hPXR) and CAR (hCAR) in the regulation of P-gp expression at the human BBB is unknown. In this study, we investigate the role of hPXR and hCAR in the regulation of P-gp expression using a human cerebral microvessel endothelial cell culture system. We demonstrate that activation of hPXR and hCAR by their respective ligands leads to P-gp induction at both mRNA and protein levels, while pharmacological inhibitors of hPXR and hCAR prevent ligand-mediated P-gp induction. Ligand-induced nuclear translocation of hPXR is observed, although such effect could not be demonstrated for hCAR. Furthermore, down-regulation of hPXR and hCAR proteins using small-interfering RNA decreased P-gp expression. Our findings provide first evidence for P-gp regulation by hPXR and hCAR at the human BBB and suggest insights on how to achieve selective P-gp regulation at this site.