Multidrug Resistance-Associated Proteins: Expression and Function in the Central Nervous System
- 19 May 2006
- journal article
- review article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 58 (2), 140-161
- https://doi.org/10.1124/pr.58.2.3
Abstract
Drug delivery to the brain is highly restricted, since compounds must cross a series of structural and metabolic barriers to reach their final destination, often a cellular compartment such as neurons, microglia, or astrocytes. The primary barriers to the central nervous system are the blood-brain and blood-cerebrospinal fluid barriers. Through structural modifications, including the presence of tight junctions that greatly limit paracellular transport, the cells that make up these barriers restrict diffusion of many pharmaceutically active compounds. In addition, the cells that comprise the blood-brain and blood-cerebrospinal fluid barriers express multiple ATP-dependent, membrane-bound, efflux transporters, such as members of the multidrug resistance-associated protein (MRP) family, which contribute to lowered drug accumulation. A relatively new concept in brain drug distribution just beginning to be explored is the possibility that cellular components of the brain parenchyma could act as a “second” barrier to brain permeation of pharmacological agents via expression of many of the same transporters. Indeed, efflux transporters expressed in brain parenchyma may facilitate the overall export of xenobiotics from the central nervous system, essentially handing themoff to the barrier tissues. We propose that these primary and secondary barriers work in tandem to limit overall accumulation and distribution of xenobiotics in the central nervous system. The present review summarizes recent knowledge in this area and emphasizes the clinical significance of MRP transporter expression in a variety of neurological disorders.Keywords
This publication has 243 references indexed in Scilit:
- Tissue distribution and induction of the rat multidrug resistance-associated proteins 5 and 6Life Sciences, 2006
- Multidrug resistance associated protein 1 protects against bilirubin‐induced cytotoxicityFEBS Letters, 2006
- Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanismProgress in Neurobiology, 2005
- Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virusVirus Research, 2005
- Rat multidrug resistance protein 4 (Mrp4, Abcc4): molecular cloning, organ distribution, postnatal renal expression, and chemical inducibilityBiochemical and Biophysical Research Communications, 2004
- Ritonavir induces P-glycoprotein expression, multidrug resistance-associated protein (MRP1) expression, and drug transporter-mediated activity in a human intestinal cell lineJournal of Pharmaceutical Sciences, 2001
- Multiple Splicing Variants of Two New Human ATP-Binding Cassette Transporters, ABCC11 and ABCC12Biochemical and Biophysical Research Communications, 2001
- Transport of Fluorescein in MDCKII-MRP1 Transfected Cells and mrp1-Knockout MiceBiochemical and Biophysical Research Communications, 2001
- Multidrug resistance-associated protein 1 (MRP1) expression in neuroblastoma cell lines and primary tumorsMedical and Pediatric Oncology, 2000
- Cerebral and pial microvessels: differential expression of γ-glutamyl transpeptidase and alkaline phosphataseBrain Structure and Function, 1999