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Originally published In Press as doi:10.1074/jbc.M004584200 on August 14, 2000

J. Biol. Chem., Vol. 275, Issue 44, 34166-34172, November 3, 2000
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Functional Reconstitution of Substrate Transport by Purified Multidrug Resistance Protein MRP1 (ABCC1) in Phospholipid Vesicles*

Qingcheng Mao, Roger G. DeeleyDagger , and Susan P. C. Cole§

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

The 190-kDa multidrug resistance protein MRP1 (ABCC1) is a polytopic transmembrane protein belonging to the ATP-binding cassette transporter superfamily. In addition to conferring resistance to various antineoplastic agents, MRP1 is a transporter of conjugated organic anions, including the cysteinyl leukotriene C4 (LTC4). We previously characterized the ATPase activity of reconstituted immunoaffinity-purified native MRP1 and showed it could be stimulated by its organic anion substrates (Mao, Q., Leslie, E. M., Deeley, R. G., and Cole, S. P. C. (1999) Biochim. Biophys. Acta 1461, 69-82). Here we show that purified reconstituted MRP1 is also capable of active transport of its substrates. Thus LTC4 uptake by MRP1 proteoliposomes was osmotically sensitive and could be inhibited by two MRP1-specific monoclonal antibodies. LTC4 uptake was also markedly reduced by the competitive inhibitor, S-decyl-glutathione, as well as by the MRP1 substrates 17beta -estradiol 17-beta -(D-glucuronide), oxidized glutathione, and vincristine in the presence of reduced glutathione. The Km for ATP and LTC4 were 357 ± 184 µM and 366 ± 38 nM, respectively, and 2.14 ± 0.75 µM for 17beta -estradiol 17-beta -(D-glucuronide). Transport of vincristine required the presence of both ATP and GSH. Conversely, GSH transport was stimulated by vincristine and verapamil. Our data represent the first reconstitution of transport competent purified native MRP1 and confirm that MRP1 is an efflux pump, which can transport conjugated organic anions and co-transport vincristine together with GSH.

* This work was supported in part by Grant MT-10519 from the Medical Research Council of Canada.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Stauffer Research Professor of Queen's University.

§ Senior Scientist of Cancer Care Ontario. To whom correspondence should be addressed: Cancer Research Laboratories, Rm. 328, Botterell Hall, Queen's University, Kingston, Ontario K7L 3N6, Canada. Tel.: 613-533-6507; Fax: 613-533-6830; E-mail: coles@post.queensu.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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