Bauer Björn, Hartz Anika M S, Fricker Gert, Miller David S
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Mol Pharmacol. 2004 Sep;66(3):413-9. doi: 10.1124/mol.66.3..
P-glycoprotein, an ATP-driven drug export pump, is a critical, selective component of the blood-brain barrier responsible for the poor penetration of many therapeutic drugs. In liver, ligand-activated, nuclear receptors are transcriptional regulators of drug metabolizing enzymes and drug export pumps, but only one, the pregnane X receptor (PXR in rodents, SXR in humans), regulates p-glycoprotein expression. We report for the first time that PXR is expressed in rat brain capillaries. Moreover, exposing isolated capillaries to the PXR ligands pregnenolone-16alpha-carbonitrile (PCN) and dexamethasone increased p-glycoprotein expression and p-glycoprotein-specific transport of a fluorescent cyclosporine A derivative into capillary lumens. Dosing rats with PCN and dexamethasone increased p-glycoprotein expression in liver plasma membranes and in brain capillaries and up-regulated specific transport in capillaries. This is the first evidence for PXR expression in brain and for regulation by nuclear receptors of a xenobiotic export pump at the blood-brain barrier. These results imply selective tightening of the barrier in patients exposed to the wide range of xenobiotics that are PXR/SXR ligands, including drugs, dietary constituents, and toxicants.
P-糖蛋白是一种由ATP驱动的药物外排泵，是血脑屏障的关键选择性成分，导致许多治疗药物难以穿透血脑屏障。在肝脏中，配体激活的核受体是药物代谢酶和药物外排泵的转录调节因子，但只有一种，即孕烷X受体（在啮齿动物中为PXR，在人类中为SXR），调节P-糖蛋白的表达。我们首次报道PXR在大鼠脑毛细血管中表达。此外，将分离的毛细血管暴露于PXR配体孕烯醇酮-16α-腈（PCN）和地塞米松中，可增加P-糖蛋白的表达以及一种荧光环孢素A衍生物向毛细血管腔的P-糖蛋白特异性转运。给大鼠注射PCN和地塞米松可增加肝细胞膜和脑毛细血管中P-糖蛋白的表达，并上调毛细血管中的特异性转运。这是PXR在脑中表达以及血脑屏障处核受体对异生物外排泵进行调节的首个证据。这些结果表明，在接触包括药物、饮食成分和毒物在内的多种PXR/SXR配体异生物的患者中，血脑屏障会有选择性地收紧。
