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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Choroid plexus epithelial expression of MDRI P glycoprotein and multidrug resistance-associated protein contribute to the blood- cerebrospinal-fluid drug-permeability barrier
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Choroid plexus epithelial expression of MDRI P glycoprotein and multidrug resistance-associated protein contribute to the blood- cerebrospinal-fluid drug-permeability barrier

机译：MDRI P糖蛋白和多药耐药相关蛋白的脉络丛上皮表达有助于血脑脊液药物通透性障碍

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摘要

The blood-brain barrier and a blood- cerebrospinal-fluid (CSF) barrier function together to isolate the brain from circulating drugs, toxins, and xenobioties. 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 expres- sion of the MDRI (multidrug resistance) P glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP). Nonin. vasive single-photon-emission computed tomography with~ 99m Tc- 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 epithe- Iium in humans in vivo. In rats, pharmacoklnetic analysis with~ 99m Tc-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 mdrla/Ib(- / -) 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 pcrmeation barrier to radiolabeled drugs. Con- versely, MRP Iocalizcs basolaterally, conferring an opposing basal-to-apical dru
机译：血脑屏障和血脑脊髓液（CSF）屏障共同发挥作用，将大脑与循环药物，毒素和异种生物隔离开来。血液-CSF药物渗透性屏障位于脉络丛（CP）的上皮。但是，调节药物跨CP上皮渗透性的分子机制定义不清。本文中，我们描述了由MDRI（多药抗性）P糖蛋白（Pgp）和多药抗性相关蛋白（MRP）的上皮特异性表达介导的人和啮齿类动物CP的药物渗透性屏障。诺宁。约99m Tc-sestamibi（一种透过膜的放射性药物，其转运受Pgp和MRP共同介导）的有功单光子发射计算机断层扫描显示，人体中完整CP上皮中血液与CSF的浓度梯度较大。 。在大鼠中，用〜99m Tc-司他米比进行药代动力学分析，确定浓度梯度大于100倍。在从大鼠，小鼠和人分离出的天然CP的膜级分中，可以轻松鉴定出170 kDa Pgp和190 kda MRP。此外，鼠蛋白不在从它们各自的mdrla / Ib（-/-）和mrp（-/-）基因敲除同窝仔中分离得到的CP中。通过对天然CP和衍生自新生大鼠CP的极化上皮细胞培养物的免疫组织化学和药物转运分析确定，PgP定位在根尖以下，为放射标记的药物赋予了根尖至基底的上皮膜渗透屏障。相反，MRP Iocalizcs基底外侧，赋予相反的基底到顶端皮肤

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