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 a nd selected glucuronide or glutathione conjugates out of the cell. The current study presents, for the first time, both functional and bioch emical data demonstrating the presence of MRP in the brain microvessel endothelial cells that form the blood-brain barrier (BBB). Using know n MRP inhibitors, such as indomethacin and probenecid, fluorescein acc umulation in primary cultured bovine brain microvessel endothelial cel l (BBMEC) monolayers was significantly enhanced compared to control. T he specificity of the MRP inhibitors on cellular fluorescein accumulat ion was confirmed using both MRP positive (Panc-1) and MRP negative (K Bv) cell lines. Furthermore, western blot analysis using a specific an tibody for MRP (MRPm6) and RT-PCR studies using a complementary sequen ce probe for human MRP demonstrate the expression of MRP in BBMEC. Pre vious studies have demonstrated the significance of the P-glycoprotein drug efflux transporter in the BBB. Given its function as a drug effl ux transport system, it is anticipated that MRP in the BBB will also h ave an important role in limiting the exposure of the brain to many en dogenous and exogenous compounds, including both toxic and therapeutic agents. (C) 1998 Academic Press.