Rao V V, Dahlheimer J L, Bardgett M E, Snyder A Z, Finch R A, Sartorelli A C, Piwnica-Worms D
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3900-5. doi: 10.1073/pnas.96.7.3900.
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 99mTc-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 99mTc-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.
血脑屏障和血脑脊液（CSF）屏障共同作用，使大脑与循环中的药物、毒素和外源性物质隔离开来。血脑脊液药物渗透屏障定位于脉络丛（CP）上皮。然而，调节药物穿过CP上皮的分子机制尚不清楚。在此，我们描述了人类和啮齿动物CP中的一种药物渗透屏障，其由MDR1（多药耐药）P糖蛋白（Pgp）和多药耐药相关蛋白（MRP）的上皮特异性表达介导。使用99mTc- sestamibi进行的无创单光子发射计算机断层扫描，99mTc- sestamibi是一种膜渗透性放射性药物，其转运由Pgp和MRP共同介导，显示在体内人类完整的CP上皮中存在较大的血脑脊液浓度梯度。在大鼠中，用99mTc- sestamibi进行药代动力学分析确定浓度梯度大于100倍。在从大鼠、小鼠和人类分离的天然CP的膜组分中，很容易鉴定出170 kDa的Pgp和190 kDa的MRP。此外，在从各自的mdr1a/1b（-/-）和mrp（-/-）基因敲除同窝仔鼠分离的CP中不存在鼠类蛋白。通过对天然CP和源自新生大鼠CP的极化上皮细胞培养物进行免疫组织化学和药物转运分析确定，Pgp定位于顶端下，赋予放射性标记药物从顶端到基底的跨上皮渗透屏障。相反，MRP定位于基底外侧，赋予相反的从基底到顶端的药物渗透屏障。总之，这些转运蛋白可能协调天然产物底物和治疗药物（包括化疗药物、抗精神病药物和HIV蛋白酶抑制剂）进出中枢神经系统的分泌和重吸收。
