QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.108.049080v1 74/6/1630    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rothnie, A. Articles by Cole, S. P. C. Search for Related Content PubMed PubMed Citation Articles by Rothnie, A. Articles by Cole, S. P. C.

Mechanistic Differences between GSH Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) and GSH Modulation of MRP1-Mediated Transport

Division of Cancer Biology & Genetics, Queen's University Cancer Research Institute, Kingston, Ontario, Canada,

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent polytopic membrane protein that transports many anticancer drugs and organic anions. Its transport mechanism is multifaceted, especially with respect to the participation of GSH. For example, vincristine is cotransported with GSH, estrone sulfate transport is stimulated by GSH, or MRP1 can transport GSH alone, and this can be stimulated by compounds such as verapamil or apigenin. Thus, the interactions between GSH and MRP1 are mechanistically complex. To examine the similarities and differences among the various GSH-associated mechanisms of MRP1 transport, we have measured first the effect of GSH and several GSH-associated substrates/modulators on the binding and hydrolysis of ATP by MRP1 using 8-azidoadenosine-5'-[³²P]-triphosphate ([³²P]azidoATP) analogs, and second the initial binding of GSH and GSH-associated substrates/modulators to MRP1. We observed that GSH or its nonreducing derivative S-methylGSH (S-mGSH), but none of the GSH-associated substrate/modulators, caused a significant increase in [-³²P]azidoATP labeling of MRP1. Moreover, GSH and S-mGSH decreased levels of orthovanadate-induced trapping of [-³²P]azidoADP. [-³²P]azidoADP.Vi trapping was also decreased by estone sulfate, whereas vincristine, verapamil, and apigenin had no apparent effects on nucleotide interactions with MRP1. Furthermore, estrone sulfate and S-mGSH enhanced the effect of each other 15- and 10-fold, respectively. Second, although GSH binding increased the apparent affinity of MRP1 for all GSH-associated substrates/modulators tested, only estrone sulfate had a reciprocal effect on the apparent affinity of MRP1 for GSH. Overall, these results indicate significant mechanistic differences between MRP1-mediated transport of GSH and the ability of GSH to modulate MRP1 transport.

Address correspondence to: Dr. Susan P. C. Cole, Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, ON, Canada, K7L 3N6. E-mail: spc.cole{at}queensu.ca

This article has been cited by other articles:

				K. Maeno, A. Nakajima, G. Conseil, A. Rothnie, R. G. Deeley, and S. P. C. Cole Molecular Basis for Reduced Estrone Sulfate Transport and Altered Modulator Sensitivity of Transmembrane Helix (TM) 6 and TM17 Mutants of Multidrug Resistance Protein 1 (ABCC1) Drug Metab. Dispos., July 1, 2009; 37(7): 1411 - 1420. [Abstract] [Full Text] [PDF]