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J. Biol. Chem., Vol. 278, Issue 32, 29509-29514, August 8, 2003
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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.
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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