Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues

Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the MRP subfamily, which in turn is a member of the superfamily of ATP-binding-cassette (ABC) transporters. Within the MRP subfamily, ABCC4,ABCC5 (MRP5), ABCC11 (MRP8) and ABCC12 (MRP9) have similar predicted membrane topologies. All lack th...

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Bibliographic Details
Published in:Biochemical journal 2002-02, Vol.361 (Pt 3), p.497-503
Main Authors: Lai, Liqi, Tan, Theresa M C
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Biological Transport
Blotting, Western
Cell Line
Cloning, Molecular
Cyclic AMP - metabolism
Dogs
Glutathione - chemistry
Glutathione - metabolism
Glutathione - physiology
Humans
Immunoblotting
Microscopy, Fluorescence
Multidrug Resistance-Associated Proteins
Protein Structure, Tertiary
Purines - chemistry
Ribosomal Proteins - chemistry
Transfection
Tumor Cells, Cultured
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Summary:Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the MRP subfamily, which in turn is a member of the superfamily of ATP-binding-cassette (ABC) transporters. Within the MRP subfamily, ABCC4,ABCC5 (MRP5), ABCC11 (MRP8) and ABCC12 (MRP9) have similar predicted membrane topologies. All lack the additional transmembrane domain, TMD(0), which is present in the other MRPs. Using cells stably overexpressing ABCC4, this study shows that ABCC4 exports GSH. ABCC4 also facilitates the efflux of cAMP. Depletion of intracellular GSH with DL-buthionine-(S,R)-sulphoximine led to decreased export of cAMP and a corresponding increase in intracellular cAMP was observed. ABCC4 also mediates resistance to purine analogues 9-(2-phosphonylmethoxyethyl)-adenine and 6-thioguanine. This resistance can be reversed by the presence of DL-buthionine-(S,R)-sulphoximine. We conclude that as well as nucleotide and nucleoside analogues, ABCC4 can mediate the export of GSH. In addition, GSH plays an important role in the function of ABCC4. Depletion of intracellular GSH adversely affects the export of cAMP by ABCC4. Resistance to nucleoside analogues is also adversely affected by depletion of cellular GSH.
ISSN:0264-6021
1470-8728
DOI:10.1042/0264-6021:3610497