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Originally published In Press as doi:10.1074/jbc.M304059200 on May 22, 2003

J. Biol. Chem., Vol. 278, Issue 32, 29509-29514, August 8, 2003
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MRP8, ATP-binding Cassette C11 (ABCC11), Is a Cyclic Nucleotide Efflux Pump and a Resistance Factor for Fluoropyrimidines 2',3'-Dideoxycytidine and 9'-(2'-Phosphonylmethoxyethyl)adenine*

Yanping Guo, Elena Kotova, Zhe-Sheng Chen {ddagger}, Kun Lee, Elizabeth Hopper-Borge, Martin G. Belinsky and Gary D. Kruh §

From the Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

MRP8 (ABCC11) is a recently identified cDNA that has been assigned to the multidrug resistance-associated protein (MRP) family of ATP-binding cassette transporters, but its functional characteristics have not been determined. Here we examine the functional properties of the protein using transfected LLC-PK1 cells. It is shown that ectopic expression of MRP8 reduces basal intracellular levels of cAMP and cGMP and enhances cellular extrusion of cyclic nucleotides in the presence or absence of stimulation with forskolin or SIN-1A. Analysis of the sensitivity of MRP8-overexpressing cells revealed that they are resistant to a range of clinically relevant nucleotide analogs, including the anticancer fluoropyrimidines 5'-fluorouracil (~3-fold), 5'-fluoro-2'-deoxyuridine (~5-fold), and 5'-fluoro-5'-deoxyuridine (~3-fold), the anti-human immunodeficiency virus agent 2',3'-dideoxycytidine (~6-fold) and the anti-hepatitis B agent 9'-(2'-phosphonylmethoxynyl)adenine (PMEA) (~5-fold). By contrast, increased resistance was not observed for several natural product chemotherapeutic agents. In accord with the notion that MRP8 functions as a drug efflux pump for nucleotide analogs, MRP8-transfected cells exhibited reduced accumulation and increased efflux of radiolabeled PMEA. In addition, it is shown by the use of in vitro transport assays that MRP8 is able to confer resistance to fluoropyrimidines by mediating the MgATP-dependent transport of 5'-fluoro-2'-deoxyuridine monophosphate, the cytotoxic intracellular metabolite of this class of agents, but not of 5'-fluorouracil or 5'-fluoro-2'-deoxyuridine. We conclude that MRP8 is an amphipathic anion transporter that is able to efflux cAMP and cGMP and to function as a resistance factor for commonly employed purine and pyrimidine nucleotide analogs.


Received for publication, April 17, 2003 , and in revised form, May 20, 2003.

* This work was supported in part by NCI, National Institutes of Health, Grants CA73728 (to G. D. K.) and CA06927 and by an appropriation from the Commonwealth of Pennsylvania. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} Recipient of a W. J. Avery Fellowship from the Fox Chase Cancer Center and a Japan Research Foundation Award for Clinical Pharmacology.

§ To whom correspondence should be addressed. Tel: 215-728-5317; Fax: 215-728-3603; E-mail: GD_Kruh{at}fccc.edu.


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