Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier

The blood-brain barrier and a blood-cerebrospinal-fluid (CSF) barrier funct ion together to isolate the brain from circulating drugs, toxins, and xenob iotics. The blood-CSF drug-permeability barrier is localized to the epithel ium of the choroid plexus (CP), However, the molecular mechanisms regulatin g drug permeability across the CP epithelium are defined poorly. Herein, we describe a drug-permeability barrier in human and rodent CP mediated by ep ithelial-specific expression of the MDR1 (multidrug resistance) P glycoprot ein (Pgp) and the multidrug resistance-associated protein (MRP), Noninvasiv e single-photon-emission computed tomography with Tc-99m-sestamibi, a membr ane-permeant radiopharmaceutical whose transport is mediated by both Pgp an d MRP, shows a large blood-to-CSF concentration gradient across intact CP e pithelium 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, t he 170-kDa Pgp and 190-kDa MRP are identified readily. Furthermore, the mur ine proteins are absent in CP isolated from their respective mdr1a/1b(-/-) and mrp(-/-) gene knockout littermates. As determined by immunohistochemica l and drug-transport analysis of native CP and polarized epithelial cell cu ltures 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 d rugs, including chemotherapeutic agents, antipsychotics, and HIV protease i nhibitors, into and out of the central nervous system.