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Characterization of Vincristine Transport by the M_r 190,000 Multidrug Resistance Protein (MRP): Evidence for Cotransport with Reduced Glutathione¹

Cancer Research Laboratories, Queen's University, Kingston, Ontario, Canada K7L 3N6

The M_r 190,000 multidrug resistance protein (MRP) confers resistance to a broad spectrum of natural product drugs. However, it has not been possible to demonstrate that MRP can actively transport unmodified forms of these compounds, although the protein has been shown to transport structurally diverse glutathione (GSH)- and glucuronide-conjugated molecules. Previously, we showed that ATP-dependent uptake of vincristine by MRP-enriched, inside-out membrane vesicles could be stimulated by physiological concentrations of GSH (Loe et al., J. Biol. Chem., 271: 9675–9682, 1996). We have now established that the ATP/GSH dependent vincristine uptake is both proportional to the level of MRP in the membrane vesicles and can be inhibited by monoclonal antibodies shown previously to inhibit transport of established MRP substrates, such as leukotriene C₄. We also show that short-chain alkyl derivatives of GSH can stimulate drug uptake, which suggests that vincristine transport does not necessarily involve a change in redox state or glutathionylation of the protein. Furthermore, vincristine uptake is accompanied by ATP- and drug-dependent accumulation of GSH, which can also be stimulated to a lesser extent by vinblastine but not daunorubicin or doxorubicin. Although GSH or vincristine alone are very poor inhibitors of MRP-mediated transport of leukotriene C₄, together they act as relatively potent competitive inhibitors. Overall, our data demonstrate that MRP can actively cotransport GSH and unmodified vincristine and that these compounds probably interact, either with the leukotriene C₄ binding site(s) on the protein or with a mutually exclusive site.

¹ Supported by Grant MT-10519 from the Medical Research Council of Canada. R. G. D. is the Stauffer Research Professor of Queen's University, and S. P. C. C. is a Senior Scientist of Cancer Care Ontario.

² To whom requests for reprints should be addressed, at Cancer Research Laboratories, Room 328, Botterell Hall, Queen's University, Kingston, Ontario, Canada, K7L 3N6. Phone: (613) 545-6507; Fax: (613) 545-6830; E-mail: coles@post.queensu.ca.

Received 3/24/98. Accepted 9/16/98.

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				D. R. Hipfner, Q. Mao, W. Qiu, E. M. Leslie, M. Gao, R. G. Deeley, and S. P. C. Cole Monoclonal Antibodies That Inhibit the Transport Function of the 190-kDa Multidrug Resistance Protein, MRP. LOCALIZATION OF THEIR EPITOPES TO THE NUCLEOTIDE-BINDING DOMAINS OF THE PROTEIN J. Biol. Chem., May 28, 1999; 274(22): 15420 - 15426. [Abstract] [Full Text] [PDF]

				K. Nagata, M. Nishitani, M. Matsuo, N. Kioka, T. Amachi, and K. Ueda Nonequivalent Nucleotide Trapping in the Two Nucleotide Binding Folds of the Human Multidrug Resistance Protein MRP1 J. Biol. Chem., June 2, 2000; 275(23): 17626 - 17630. [Abstract] [Full Text] [PDF]

				Y.-x. Hou, L. Cui, J. R. Riordan, and X.-b. Chang Allosteric Interactions between the Two Non-equivalent Nucleotide Binding Domains of Multidrug Resistance Protein MRP1 J. Biol. Chem., June 30, 2000; 275(27): 20280 - 20287. [Abstract] [Full Text] [PDF]

				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]

				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]

				R. Daoud, M. Julien, P. Gros, and E. Georges Major Photoaffinity Drug Binding Sites in Multidrug Resistance Protein 1 (MRP1) Are within Transmembrane Domains 10-11 and 16-17 J. Biol. Chem., April 6, 2001; 276(15): 12324 - 12330. [Abstract] [Full Text] [PDF]

				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]

				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]

				M. F. Rosenberg, Q. Mao, A. Holzenburg, R. C. Ford, R. G. Deeley, and S. P. C. Cole The Structure of the Multidrug Resistance Protein 1 (MRP1/ABCC1). CRYSTALLIZATION AND SINGLE-PARTICLE ANALYSIS J. Biol. Chem., May 4, 2001; 276(19): 16076 - 16082. [Abstract] [Full Text] [PDF]

				X.-Q. Ren, T. Furukawa, S. Aoki, T. Nakajima, T. Sumizawa, M. Haraguchi, Z.-S. Chen, M. Kobayashi, and S.-i. Akiyama Glutathione-dependent Binding of a Photoaffinity Analog of Agosterol A to the C-terminal Half of Human Multidrug Resistance Protein J. Biol. Chem., June 15, 2001; 276(25): 23197 - 23206. [Abstract] [Full Text] [PDF]

				D.-W. Zhang, S. P. C. Cole, and R. G. Deeley Identification of a Nonconserved Amino Acid Residue in Multidrug Resistance Protein 1 Important for Determining Substrate Specificity. EVIDENCE FOR FUNCTIONAL INTERACTION BETWEEN TRANSMEMBRANE HELICES 14 AND 17 J. Biol. Chem., September 7, 2001; 276(37): 34966 - 34974. [Abstract] [Full Text] [PDF]

				J. Wijnholds, C. A. A. M. Mol, L. van Deemter, M. de Haas, G. L. Scheffer, F. Baas, J. H. Beijnen, R. J. Scheper, S. Hatse, E. De Clercq, et al. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs PNAS, June 20, 2000; 97(13): 7476 - 7481. [Abstract] [Full Text] [PDF]