Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / metabolism*
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Adenosine Monophosphate / pharmacology
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Biological Transport / drug effects
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Carcinoma, Non-Small-Cell Lung
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Cell Membrane / metabolism
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Drug Resistance, Multiple
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Ethacrynic Acid / metabolism*
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Glutathione / metabolism*
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Glutathione / pharmacology
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Humans
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Kinetics
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Lung Neoplasms
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Multidrug Resistance-Associated Proteins
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae / metabolism
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Sulfinpyrazone / pharmacology
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Transfection
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Tumor Cells, Cultured
Substances
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ATP-Binding Cassette Transporters
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Multidrug Resistance-Associated Proteins
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Recombinant Proteins
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Adenosine Monophosphate
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Glutathione
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Ethacrynic Acid
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Sulfinpyrazone