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Originally published In Press as doi:10.1074/jbc.M011246200 on February 21, 2001

J. Biol. Chem., Vol. 276, Issue 19, 15616-15624, May 11, 2001
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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*

Ken-ichi Ito, Sharon L. OlsenDagger , Wei Qiu, Roger G. Deeley, and Susan P. C. Cole§

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

Multidrug resistance protein 1 (MRP1/ABCC1) belongs to the ATP-binding cassette transporter superfamily and is capable of conferring resistance to a broad range of chemotherapeutic agents and transporting structurally diverse conjugated organic anions. In this study, we found that substitution of a highly conserved tryptophan at position 1246 with cysteine (W1246C-MRP1) in the putative last transmembrane segment (TM17) of MRP1 eliminated 17beta -estradiol 17-(beta -D-glucuronide) (E217beta G) transport by membrane vesicles prepared from transiently transfected human embryonic kidney cells while leaving the capacity for leukotriene C4- and verapamil-stimulated glutathione transport intact. In addition, in contrast to wild-type MRP1, leukotriene C4 transport by the W1246C-MRP1 protein was no longer inhibitable by E217beta G, indicating that the mutant protein had lost the ability to bind the glucuronide. A similar phenotype was observed when Trp1246 was replaced with Ala, Phe, and Tyr. Confocal microscopy of cells expressing Trp1246 mutant MRP1 molecules fused at the C terminus with green fluorescent protein showed that they were correctly routed to the plasma membrane. In addition to the loss of E217beta G transport, HeLa cells stably transfected with W1246C-MRP1 cDNA were not resistant to the Vinca alkaloid vincristine and accumulated levels of [3H]vincristine comparable to those in vector control-transfected cells. Cells expressing W1246C-MRP1 were also not resistant to cationic anthracyclines (doxorubicin, daunorubicin) or the electroneutral epipodophyllotoxin VP-16. In contrast, resistance to sodium arsenite was only partially diminished, and resistance to potassium antimony tartrate remained comparable to that of cells expressing wild-type MRP1. This suggests that the structural determinants required for transport of heavy metal oxyanions differ from those for chemotherapeutic agents. Our results provide the first example of a tryptophan residue being so critically important for substrate specificity in a eukaryotic ATP-binding cassette transporter.

* This work was supported by Grant MT-10519 from the Medical Research Council of Canada (Canadian Institutes for Health Research).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 Recipient of a fellowship from the International Agency for Cancer Research.

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

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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