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Vol. 62, Issue 6, 1321-1331, December 2002
Division of Molecular Biology and Center for Biomedical Genetics
(P.R.W., G.R., I.v.d.H., L.v.D., M.d.H., C.M., A.J.K., J.W., P.B.) and
Division of Tumor Biology (E.G.), The Netherlands Cancer Institute,
Amsterdam, the Netherlands; Department of Pharmacy and Pharmacology,
Slotervaart Hospital, Amsterdam, the Netherlands (E.E.C., J.H.B.);
Department of Pharmaceutical Sciences, St Jude Children's Research
Hospital, Memphis, Tennessee (J.D.S.); and St. Radboud Academic
Hospital, Nijmegen, the Netherlands (C.B., R.A.D.)
Mercaptopurines have been used as anticancer agents for more
than 40 years, and most acute lymphoblastic leukemias are treated with
6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two
related multidrug resistance proteins MRP4 and MRP5 has been shown to
confer some resistance against mercaptopurines, which has been
attributed to extrusion of mercaptopurine metabolites by these
transporters. We have analyzed the mercaptopurine metabolites formed in
human embryonic kidney cells and determined which metabolites are
extruded by MRP4 and MRP5. Incubation with 6MP led to the formation of
thioinosine and thioxanthosine metabolites and we found that thio-IMP
was transported by both MRP4 and MRP5; MRP5 showed the highest
transport rate. In contrast, only MRP5 transported thioxanthosine
monophosphate (tXMP). During incubation with TG, the monophosphorylated
form of thioguanosine was transported by both MRP4 and MRP5; the
highest transport rate was for MRP4. Similarly, only 6-methyl-thio-IMP
was formed during incubation with 6-methyl mercaptopurine riboside.
This compound was a substrate for both MRP4 and MRP5; MRP4 showed the
highest transport rate. Our results show that all major thiopurine
monophosphates important in the efficacy of mercaptopurine treatment
are transported by MRP4 and MRP5, although the substrate specificity of
the two transporters differs in detail.
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