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Vol. 293, Issue 2, 530-538, May 2000
Cancer Research Laboratories, Queen's University, Kingston,
Ontario, Canada
Multidrug resistance in tumor cells is often associated with reduced
drug accumulation resulting from increased expression of the 190-kDa
multidrug resistance protein 1 (MRP1) or the 170-kDa P-glycoprotein.
However, unlike P-glycoprotein, MRP1 is a primary active transporter of
many conjugated organic anions, including the cysteinyl leukotriene
LTC4. Moreover, agents such as verapamil that reverse
P-glycoprotein-mediated resistance are often poorly, or not at all,
effective in MRP1-overexpressing cells. In the present study, we
investigated the effects of verapamil on MRP1-mediated transport
processes. We found that verapamil inhibited LTC4 transport into inside-out membrane vesicles prepared from MRP1-transfected cells
in a competitive manner, but only in the presence of reduced glutathione (GSH) or its nonreducing S-methyl
derivative. In the presence of 1 mM GSH, the apparent
Ki for verapamil was 1.2 µM, and in the
presence of 100 µM verapamil, the apparent
Ki for GSH was 77 µM. Verapamil itself was
not transported by MRP1 in either intact cells or membrane vesicles.
However, verapamil strongly stimulated MRP1-mediated GSH uptake by
membrane vesicles in a concentration-dependent and osmotically
sensitive manner that was inhibitable by MRP1-specific monoclonal
antibodies. In the presence of 100 µM verapamil, the apparent
Km and Vmax for
GSH uptake were 83 µM and 55 pmol mg
1
min1, respectively. It is proposed that the variable
ability of verapamil to modulate MRP1-mediated resistance in different
cell lines may be more closely linked to its effect on the GSH status
of the cells than on its ability to inhibit the MRP1 transporter itself.
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N. Zelcer, M. T. Huisman, G. Reid, P. Wielinga, P. Breedveld, A. Kuil, P. Knipscheer, J. H. M. Schellens, A. H. Schinkel, and P. Borst Evidence for Two Interacting Ligand Binding Sites in Human Multidrug Resistance Protein 2 (ATP Binding Cassette C2) J. Biol. Chem., June 20, 2003; 278(26): 23538 - 23544. [Abstract] [Full Text] [PDF]
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K. Koike, C. J. Oleschuk, A. Haimeur, S. L. Olsen, R. G. Deeley, and S. P. C. Cole Multiple Membrane-associated Tryptophan Residues Contribute to the Transport Activity and Substrate Specificity of the Human Multidrug Resistance Protein, MRP1 J. Biol. Chem., December 13, 2002; 277(51): 49495 - 49503. [Abstract] [Full Text] [PDF]
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A. Haimeur, R. G. Deeley, and S. P. C. Cole Charged Amino Acids in the Sixth Transmembrane Helix of Multidrug Resistance Protein 1 (MRP1/ABCC1) Are Critical Determinants of Transport Activity J. Biol. Chem., October 25, 2002; 277(44): 41326 - 41333. [Abstract] [Full Text] [PDF]
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Y.-M. Qian, C. E. Grant, C. J. Westlake, D.-W. Zhang, P. A. Lander, R. L. Shepard, A. H. Dantzig, S. P. C. Cole, and R. G. Deeley Photolabeling of Human and Murine Multidrug Resistance Protein 1 with the High Affinity Inhibitor [125I]LY475776 and Azidophenacyl-[35S]Glutathione J. Biol. Chem., September 13, 2002; 277(38): 35225 - 35231. [Abstract] [Full Text] [PDF]
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Q. Mao, W. Qiu, K. E. Weigl, P. A. Lander, L. B. Tabas, R. L. Shepard, A. H. Dantzig, R. G. Deeley, and S. P. C. Cole GSH-dependent Photolabeling of Multidrug Resistance Protein MRP1 (ABCC1) by [125I]LY475776. EVIDENCE OF A MAJOR BINDING SITE IN THE COOH-PROXIMAL MEMBRANE SPANNING DOMAIN J. Biol. Chem., August 2, 2002; 277(32): 28690 - 28699. [Abstract] [Full Text] [PDF]
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E. M. Leslie, Q. Mao, C. J. Oleschuk, R. G. Deeley, and S. P. C. Cole Modulation of Multidrug Resistance Protein 1 (MRP1/ABCC1) Transport and ATPase Activities by Interaction with Dietary Flavonoids Mol. Pharmacol., April 16, 2001; 59(5): 1171 - 1180. [Abstract] [Full Text]
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Q. Mao, R. G. Deeley, and S. P. C. Cole Functional Reconstitution of Substrate Transport by Purified Multidrug Resistance Protein MRP1 (ABCC1) in Phospholipid Vesicles J. Biol. Chem., October 27, 2000; 275(44): 34166 - 34172. [Abstract] [Full Text] [PDF]
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Y.-M. Qian, W.-C. Song, H. Cui, S. P. C. Cole, and R. G. Deeley Glutathione Stimulates Sulfated Estrogen Transport by Multidrug Resistance Protein 1 J. Biol. Chem., February 23, 2001; 276(9): 6404 - 6411. [Abstract] [Full Text] [PDF]
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D.-W. Zhang, S. P. C. Cole, and R. G. Deeley Identification of an Amino Acid Residue in Multidrug Resistance Protein 1 Critical for Conferring Resistance to Anthracyclines J. Biol. Chem., April 13, 2001; 276(16): 13231 - 13239. [Abstract] [Full Text] [PDF]
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K.-i. Ito, S. L. Olsen, W. Qiu, R. G. Deeley, and S. P. C. Cole Mutation of a Single Conserved Tryptophan in Multidrug Resistance Protein 1 (MRP1/ABCC1) Results in Loss of Drug Resistance and Selective Loss of Organic Anion Transport J. Biol. Chem., May 4, 2001; 276(19): 15616 - 15624. [Abstract] [Full Text] [PDF]
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E. M. Leslie, K.-i. Ito, P. Upadhyaya, S. S. Hecht, R. G. Deeley, and S. P. C. Cole Transport of the beta -O-Glucuronide Conjugate of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the Multidrug Resistance Protein 1 (MRP1). REQUIREMENT FOR GLUTATHIONE OR A NON-SULFUR-CONTAINING ANALOG J. Biol. Chem., July 20, 2001; 276(30): 27846 - 27854. [Abstract] [Full Text] [PDF]
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