Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP.
The multidrug resistance protein MRP has been shown to mediate the transport of glutathione S-conjugates across membranes. In this study we demonstrate that the glutathione S-conjugate of the diuretic drug ethacrynic acid, which is an efficient inhibitor of glutathione S-transferases, is a high-affinity substrate and inhibitor of the glutathione S-conjugate pump associated with MRP. This implies that ethacrynic acid may modulate drug resistance of tumor cells not only by inhibiting glutathione S-transferase activity, but also by inhibiting the export of drug conjugates from the cell by MRP.
Zaman
G J
GJ
Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Cnubben
N H
NH
van Bladeren
P J
PJ
Evers
R
R
Borst
P
P
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung; D002462:Cell Membrane / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004976:Ethacrynic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013442:Sulfinpyrazone / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000249:Adenosine Monophosphate; D004976:Ethacrynic Acid; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins; D013442:Sulfinpyrazone