Potential role of ABC transporters as a detoxification system at the blood-CSF barrier.
Exchange of compounds between blood and brain occurs at two barriers, the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). The barrier function is mainly a result of the functionality of the cerebral endothelial cells and choroidal epithelial cells, respectively. These cell types have restricted permeability due to the presence of tight junctions between the cells. Furthermore, these cells express a broad range of transporters. So far, the BBB has been viewed as the most important barrier, especially as its surface is about 3 orders of magnitude larger than that of the BCSFB. Today, there is a shift in the appreciation of the contribution of the BCSFB. In a few recent studies, it has been shown that the BCSFB expresses two types of ATP-binding cassette (ABC) transporters, being the multidrug transporters P-glycoprotein (P-gp) and the multidrug resistance-related protein 1 (MRP1). The knowledge on the function of these transporters in the BCSFB is relatively scarce, but in general, it seems that MRP1 transport is directed towards the blood side, which makes this transporter helpful in elimination of harmful compounds from the CSF. Thereby MRP1 potentially contributes to detoxification of the brain, as a whole, as it is also expressed at the level of the BBB. P-gp, however, while also functional as an efflux pump at the BBB, has an opposite transport direction at the level of the BCSFB, towards the CSF. P-gp may therefore raise the concentration of neurotoxic P-gp substrates in the CSF. Whether this will have a significant contribution to the toxicity in the regions directly exposed to the CSF (periventricular organs) remains to be determined. Specifically, in the epithelial cells of the choroid plexus of the BCSFB, P-gp and MRP1 together serve a protective role by preventing the accumulation of their overlapping and often toxic substrates. A concerted action of P-gp and MRP1 at the choroid plexus might contribute to the maintenance of the role of the BCSFB in brain homeostasis.
de Lange
Elizabeth C M
EC
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratoria, Leiden University, PO BOX 9502, 2300RA Leiden, The Netherlands. L.Lange@lacdr.leidenuniv.nl
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D002831:Choroid Plexus / Q000378:metabolism; D018432:Drug Resistance, Multiple; D006801:Humans
D018528:ATP-Binding Cassette Transporters