Transporter-mediated protection against thiopurine-induced hematopoietic toxicity.

Abstract

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.

• Authors: Partha Krishnamurthy, Matthias Schwab, Kazumasa Takenaka, Deepa Nachagari, Jessica Morgan, Mark Leslie, Weinan Du, Kelli Boyd, Meyling Cheok, Hiromitsu Nakauchi, Catia Marzolini, Richard B Kim, Balasubramanian Poonkuzhali, Erin Schuetz, William Evans, Mary Relling, John D Schuetz
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 13 Pg. 4983-9 (Jul 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18593894 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCC4 protein, human
• Membrane Transport Proteins
• Multidrug Resistance-Associated Proteins
• Purines
• Sulfhydryl Compounds
• Mercaptopurine

Topics

• Alleles
• Animals
• Cell Membrane (metabolism)
• Cells, Cultured
• Cytoprotection (drug effects, genetics)
• Drug Resistance, Neoplasm (genetics)
• Hematologic Diseases (chemically induced, mortality)
• Hematopoiesis (drug effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Membrane Transport Proteins (genetics, metabolism, physiology)
• Mercaptopurine (adverse effects, pharmacology, therapeutic use)
• Mice
• Mice, Knockout
• Models, Biological
• Multidrug Resistance-Associated Proteins (genetics, metabolism, physiology)
• Polymorphism, Single Nucleotide (physiology)
• Purines (adverse effects, chemistry, therapeutic use)
• Sulfhydryl Compounds (adverse effects, therapeutic use)
• Survival Analysis
• Tissue Distribution