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 resistance to various cytotoxic drugs by lowering the intracellular drug concentration. Recent evidence indicates that MRP can also transport glutathione S-conjugates across membranes. To study the transport properties of MRP in intact ce...

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Published inThe Journal of clinical investigation Vol. 97; no. 5; pp. 1211 - 1218
Main Authors Evers, R, Zaman, G J, van Deemter, L, Jansen, H, Calafat, J, Oomen, L C, Oude Elferink, R P, Borst, P, Schinkel, A H
Format Journal Article
LanguageEnglish
Published United States 01.03.1996
Subjects
Animals
ATP-Binding Cassette Transporters - analysis
ATP-Binding Cassette Transporters - metabolism
Biological Transport
Cell Line
Daunorubicin - pharmacokinetics
Drug Resistance, Multiple
Glutathione - analogs & derivatives
Glutathione - metabolism
Humans
Kidney - chemistry
Multidrug Resistance-Associated Proteins
Swine
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Summary:The human multidrug resistance-associated protein MRP confers resistance to various cytotoxic drugs by lowering the intracellular drug concentration. Recent evidence indicates that MRP can also transport glutathione S-conjugates across membranes. To study the transport properties of MRP in intact cells, we have expressed human MRP cDNA in the polarized 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 scanning 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 probenecid, known inhibitors of multispecific organic anion transport, inhibited this basolateral transport, but not the apical transport of daunorubicin mediated by the apically localized human MDR1 P-glycoprotein in MDR1-transfected LLC-PK1 cells. Probenecid and sulfinpyrazone may therefore be useful lead compounds for the development of clinical reversal agents specific for MRP-mediated drug resistance.
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ISSN:0021-9738
DOI:10.1172/jci118535