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1 Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany; and 2 Division of Gastroenterology, Department of Medicine, University of California, San Diego, California 92093-0813
The multidrug
resistance protein 2 (MRP2, symbol ABCC2) transports anionic conjugates
and certain amphiphilic anions across the apical membrane of polarized
cells. Human hepatoma Hep G2 cells retain hepatic polarity and form
apical vacuoles into which cholephilic substances are secreted.
Immunofluorescence microscopy showed that human MRP2 was expressed in
the apical vacuole membrane of polarized Hep G2 cells, whereas the
isoform MRP3 was localized to the lateral membrane. Expression of both
MRP2 and MRP3 was confirmed by immunoblotting and reverse transcription
PCR. Fluo 3 secretion into the apical vacuoles was inhibited by
cyclosporin A but not by selective inhibitors of multidrug resistance 1 P-glycoprotein. In addition, carboxyfluorescein, rhodamine 123, and the
fluorescent bile salt derivatives
ursodeoxycholyl-(N
-nitrobenzoxadiazolyl)-lysine and
cholylglycylamido-fluorescein were secreted into the apical vacuoles;
the latter two probably via the bile salt export pump. We conclude that
MRP2 mediates fluo 3 secretion into the apical vacuoles of polarized
Hep G2 cells. Thus the function of human MRP2 and the action of
inhibitors can be analyzed by the secretion of fluorescent anions such
as fluo 3.
multidrug resistance protein 2 (ABCC2); multidrug resistance protein 3 (ABCC3); ATP-dependent transport; fluorescent bile salts; cyclosporin A
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