Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier
Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier
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DOI：
10.1073/pnas.96.7.3900
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发表时间：
1999-03-30
影响因子：
11.1
通讯作者：
Piwnica-Worms, D
中科院分区：
文献类型：
--
作者：
Rao, VV;Dahlheimer, JL;Piwnica-Worms, D
血脑屏障和血脑脊髓液（CSF）屏障共同起作用，将大脑与循环药物、毒素和外源性物质隔离。血-脑脊液药物渗透屏障位于脉络丛上皮，然而，调节药物穿过脉络丛上皮的分子机制尚不清楚。在此，我们描述了人和啮齿动物CP中由上皮特异性表达的MDR 1介导的药物渗透屏障。（多药耐药）P糖蛋白（Pgp）和多药耐药相关蛋白（MRP），使用Tc-99 m-sestamibi（一种膜渗透放射性药物，其转运由Pgp和MRP介导）的无创单光子发射计算机断层扫描，显示了人体内完整CP上皮的大的血液-CSF浓度梯度。在大鼠中，Tc-99 m-sestamibi的药代动力学分析确定浓度梯度大于100倍。在分离的天然CP从大鼠，小鼠和人类的膜组分中，170-kDa的Pgp和190-kDa的MRP很容易确定。此外，从mdr 1a/1b（-/-）和mrp（-/-）基因敲除同窝出生仔分离的CP中不存在鼠蛋白。正如所确定的免疫组织化学和药物转运分析的天然CP和极化上皮细胞培养物来自新生大鼠CP，Pgp定位subapically，赋予一个顶部到基底的经上皮渗透屏障放射性标记的药物。相反，MRP定位于基底外侧，赋予相反的基底至顶端药物渗透屏障。这些转运蛋白可以一起协调天然产物底物和治疗药物（包括化疗剂、抗精神病药和HIV蛋白酶抑制剂）的分泌和重吸收，进入和离开中枢神经系统。
The blood-brain barrier and a blood-cerebrospinal-fluid (CSF) barrier function together to isolate the brain from circulating drugs, toxins, and xenobiotics. The blood-CSF drug-permeability barrier is localized to the epithelium of the choroid plexus (CP), However, the molecular mechanisms regulating drug permeability across the CP epithelium are defined poorly. Herein, we describe a drug-permeability barrier in human and rodent CP mediated by epithelial-specific expression of the MDR1 (multidrug resistance) P glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP), Noninvasive single-photon-emission computed tomography with Tc-99m-sestamibi, a membrane-permeant radiopharmaceutical whose transport is mediated by both Pgp and MRP, shows a large blood-to-CSF concentration gradient across intact CP epithelium in humans in vivo. In rats, pharmacokinetic analysis with Tc-99m-sestamibi determined the concentration gradient to be greater than 100-fold. In membrane fractions of isolated native CP from rat, mouse, and human, the 170-kDa Pgp and 190-kDa MRP are identified readily. Furthermore, the murine proteins are absent in CP isolated from their respective mdr1a/1b(-/-) and mrp(-/-) gene knockout littermates. As determined by immunohistochemical and drug-transport analysis of native CP and polarized epithelial cell cultures derived from neonatal rat CP, Pgp localizes subapically, conferring an apical-to-basal transepithelial permeation barrier to radiolabeled drugs. Conversely, MRP localizes basolaterally, conferring an opposing basal-to apical drug-permeation barrier, Together, these transporters may coordinate secretion and reabsorption of natural product substrates and therapeutic drugs, including chemotherapeutic agents, antipsychotics, and HIV protease inhibitors, into and out of the central nervous system.