Characterization of multidrug resistance-associated protein (MRP) homologues in the blood-brain barrier (BBB)

Drug efflux transport proteins, such as P-glycoprotein (P-gp) and members of multidrug resistance-associated protein (MRP) family, are not only responsible for the multidrug resistance (MDR) during cancer chemotherapy but also have important physiological roles regarding the absorption, distribution, and elimination of compounds. The importance of P-gp in the blood-brain barrier (BBB) has been well studied, however, the function of various MRP homologues in the BBB, is still unclear. Currently, nine MRP homologues have been identified (MRP1–MRP9), six of which have been implicated in the transport of organic anions. The expression of MRP1, MRP2, and MRP5 has been demonstrated in whole brain homogenates from a few studies; however, the expression of these transporters in the BBB and their exact localization in the plasma membrane of the BBB is still unknown.; The present study demonstrated the expression of MRP1, MRP4, MRP5, and MRP6 in both the in vitro bovine brain microvessel endothelial cells (BBMEC) and the bovine brain capillary-enriched fractions isolated from fresh brain homogenates. MRP1 and MRP5 were shown to be localized on the lumenal membrane of the BBB, which resembled the localization of P-gp. In contrast, MRP4 was distributed equally on both the lumenal and the ablumenal membranes of the BBMEC. Using various MRP substrates and inhibitors, the MRP homologues that are expressed in the BBMEC were shown to be functionally active. Moreover, in the present study, the expression of various MRP homologues in both AIDS and Alzheimer's autopsies were compared to healthy human brain homogenates. The fact that both MRP4 and MRP5 expression were upregulated in the brain autopsies of AIDS and Alzheimer's patients, while other MRP homologues were well maintained at a same level, suggests an important role of these two transporters in these two disease conditions. Therefore, multiple MRP homologues that are expressed in the BBB may be important in controlling the BBB permeability under both normal and pathophysiological conditions.