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 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.
Rao
V V
VV
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Dahlheimer
J L
JL
Bardgett
M E
ME
Snyder
A Z
AZ
Finch
R A
RA
Sartorelli
A C
AC
Piwnica-Worms
D
D
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000502:physiology*; D002199:Capillary Permeability; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000502:physiology*; D002831:Choroid Plexus / Q000166:cytology / Q000502:physiology*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007624:KB Cells; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009424:Nervous System Physiological Phenomena; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics; D015899:Tomography, Emission-Computed, Single-Photon; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011994:Recombinant Proteins; D017256:Technetium Tc 99m Sestamibi