Transporter-mediated protection against thiopurine-induced hematopoietic toxicity.

Krishnamurthy P, Schwab M, Takenaka K, Nachagari D, Morgan J, Leslie M, Du W, Boyd K, Cheok M, Nakauchi H, Marzolini C, Kim RB, Poonkuzhali B, Schuetz E, Evans W, Relling M, Schuetz JD
Cancer Res. 2008 68 (13): 4983-9

PMID: 18593894 · PMCID: PMC3323115 · DOI:10.1158/0008-5472.CAN-07-6790

Thiopurines are effective immunosuppressants and anticancer agents, but intracellular accumulation of their active metabolites (6-thioguanine nucleotides, 6-TGN) causes dose-limiting hematopoietic toxicity. Thiopurine S-methyltransferase deficiency is known to exacerbate thiopurine toxicity. However, many patients are highly sensitive to thiopurines for unknown reasons. We show that multidrug-resistance protein 4 (Mrp4) is abundant in myeloid progenitors and tested the role of the Mrp4, an ATP transporter of monophosphorylated nucleosides, in this unexplained thiopurine sensitivity. Mrp4-deficient mice experienced Mrp4 gene dosage-dependent toxicity caused by accumulation of 6-TGNs in their myelopoietic cells. Therefore, Mrp4 protects against thiopurine-induced hematopoietic toxicity by actively exporting thiopurine nucleotides. We then identified a single-nucleotide polymorphism (SNP) in human MRP4 (rs3765534) that dramatically reduces MRP4 function by impairing its cell membrane localization. This SNP is common (>18%) in the Japanese population and indicates that the increased sensitivity of some Japanese patients to thiopurines may reflect the greater frequency of this MRP4 SNP.

MeSH Terms (21)

Alleles Animals Cell Membrane Cells, Cultured Cytoprotection Drug Resistance, Neoplasm Hematologic Diseases Hematopoiesis Humans Leukemia, Myeloid, Acute Membrane Transport Proteins Mercaptopurine Mice Mice, Knockout Models, Biological Multidrug Resistance-Associated Proteins Polymorphism, Single Nucleotide Purines Sulfhydryl Compounds Survival Analysis Tissue Distribution

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