Expression of multidrug resistance-associated protein (MRP) in brain microvessel endothelial cells.
Multidrug resistance-associated protein (MRP) is a recently identified drug efflux transport system that actively transports organic acids and selected glucuronide or glutathione conjugates out of the cell. The current study presents, for the first time, both functional and biochemical data demonstrating the presence of MRP in the brain microvessel endothelial cells that form the blood-brain barrier (BBB). Using known MRP inhibitors, such as indomethacin and probenecid, fluorescein accumulation in primary cultured bovine brain microvessel endothelial cell (BBMEC) monolayers was significantly enhanced compared to control. The specificity of the MRP inhibitors on cellular fluorescein accumulation was confirmed using both MRP positive (Panc-1) and MRP negative (KBv) cell lines. Furthermore, western blot analysis using a specific antibody for MRP (MRPm6) and RT-PCR studies using a complementary sequence probe for human MRP demonstrate the expression of MRP in BBMEC. Previous studies have demonstrated the significance of the P-glycoprotein drug efflux transporter in the BBB. Given its function as a drug efflux transport system, it is anticipated that MRP in the BBB will also have an important role in limiting the exposure of the brain to many endogenous and exogenous compounds, including both toxic and therapeutic agents.
Huai-Yun
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Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-6025, USA.
Secrest
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DT
Mark
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Carney
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Brandquist
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Elmquist
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Miller
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply*; D002417:Cattle; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D004730:Endothelium, Vascular / Q000378:metabolism*; D019793:Fluorescein / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008833:Microcirculation / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016133:Polymerase Chain Reaction; D011339:Probenecid / Q000494:pharmacology; D012313:RNA / Q000032:analysis; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D019793:Fluorescein; D007213:Indomethacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid; D012313:RNA