BASOLATERAL LOCALIZATION AND EXPORT ACTIVITY OF THE HUMAN MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN IN POLARIZED PIG-KIDNEY CELLS

The human multidrug resistance-associated protein MRP confers resistan ce to various cytotoxic drugs by lowering the intracellular drug conce ntration. Recent evidence indicates that MRP can also transport glutat hione S-conjugates across membranes. To study the transport properties of MRP in intact cells, we have expressed human MRP cDNA in the polar ized pig kidney epithelial cell line LLC-PK1. MRP mainly localized to the basolateral plasma membrane of these cells, and not to the apical membrane, as determined by immunocytochemistry using confocal laser sc anning and electron microscopy. In accordance with this localization, MRP caused increased transport of the glutathione S-conjugate S-(2, 4- dinitrophenyl)-glutathione and of the anticancer drug daunorubicin to the basal side of the epithelial cell layer. Sulfinpyrazone and proben ecid, known inhibitors of multispecific organic anion transport, inhib ited this basolateral transport, but not the apical transport of dauno rubicin mediated by the apically localized human MDR1 P-glycoprotein i n MDR1-transfected LLC-PK1 cells. Probenecid and sulfinpyrazone may th erefore be useful lead compounds for the development of clinical rever sal agents specific for MRP-mediated drug resistance.