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Vol. 63, Issue 5, 1094-1103, May 2003
Division of Molecular Biology and Center of Biomedical Genetics,
the Netherlands Cancer Institute, Amsterdam, the Netherlands (G.R.,
P.W., N.Z., M.d.H., L.v.D., P.B.); and Laboratory of Virology and
Chemotherapy, Rega Institute for Medical Research, Katholieke
Universiteit Leuven, Leuven, Belgium (J.B.)
The human multidrug resistance proteins MRP4 and MRP5 are organic anion
transporters that have the unusual ability to transport cyclic
nucleotides and some nucleoside monophosphate analogs. Base and
nucleoside analogs used in the chemotherapy of cancer and viral
infections are potential substrates. To assess the possible contribution of MRP4 and MRP5 to resistance against these drugs, we
have investigated the transport mediated by MRP4 and MRP5. In
cytotoxicity assays, MRP4 conferred resistance to the antiviral agent
9-(2-phosphonomethoxyethyl)adenine (PMEA) and high-performance liquid
chromatography analysis showed that, like MRP5, MRP4 transported PMEA
in an unmodified form. MRP4 also mediated substantial resistance against other acyclic nucleoside phosphonates, whereas MRP5 did not.
Apart from low-level MRP4-mediated cladribine resistance, the
cytotoxicity of clinically used anticancer nucleosides was not
influenced by overexpression of MRP4 or MRP5. In contrast, MRP5
mediated efflux of the pyrimidine-based antiviral
2',3'-dideoxynucleoside 2',3'-didehydro-2',3'-dideoxythymidine
5'-monophosphate (d4TMP) and its phosphoramidate derivative
alaninyl-d4TMP from cells loaded with the
2',3'-didehydro-2',3'-dideoxythymidine prodrugs cyclosaligenyl-d4TMP and aryloxyphosphoramidate d4TMP (So324), respectively. Moreover, only
inside-out membrane vesicles derived from MRP5-overexpressing cells
accumulated alaninyl-d4TMP. Cellular efflux and vesicular uptake
studies were carried out to further compare transport mediated by MRP4
and MRP5 and showed that dipyridamole, dilazep, nitrobenzyl mercaptopurine riboside, sildenafil, trequinsin and MK571 inhibited MRP4 more than MRP5, whereas cyclic nucleotides and monophosphorylated nucleoside analogs were equally poor inhibitors of both pumps. These
results strongly suggest that the affinity of MRP4 and MRP5 for
nucleotide-based substrates is low.
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