Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells.

Pieter Wielinga, G. Reid, E. E. Challa, I. van der Heijden, L. van Deemter, M. de Haas, C. Mol, A. J. Kuil, E. Groeneveld, J. D. Schuetz, C. Brouwer, R. A. De Abreu, J. Wijnholds, J. H. Beijnen, P. Borst

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
JournalMolecular Pharmacology
Volume62
Issue number6
Pages (from-to)1321-1331
ISSN0026-895x
Publication statusPublished - 2002
Externally publishedYes

Keywords

  • thioxanthosine monophosphate
  • acute lymphoblastic leukemia Leukemia, Lymphocytic, Acute (MeSH) blood and lymphatic disease, neoplastic disease
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] HEK293 cell line cell line embryonic kidney
  • 6-mercaptopurine 50-44-2 antineoplastic-drug resistance
  • 6-thioguanine 154-42-7 antineoplastic-drug resistance
  • multidrug resistance protein 4 MRP4
  • multidrug resistance protein 5 MRP5
  • thiopurine metabolism
  • thiopurine monophosphates
  • 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines
  • 12512, Pathology - Therapy
  • 13002, Metabolism - General metabolism and metabolic pathways
  • 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 24008, Neoplasms - Therapeutic agents and therapy
  • 24010, Neoplasms - Blood and reticuloendothelial neoplasms
  • Pharmacology
  • Tumor Biology

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