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Transporter-Mediated Protection against Thiopurine-Induced Hematopoietic Toxicity

¹ Department of Pharmaceutical Sciences and ² Animal Resource Center, St. Jude Children's Research Hospital, Memphis, Tenessee; ³ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Tuebingen, Germany; ⁴ Department of Immunology, Institute of Basic Medical Sciences, University of Tsukuba, baraki, Japan; ⁵ Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tenessee; and ⁶ Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada

Requests for reprints: John D. Schuetz, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale Avenue, Memphis, TN 38105. Phone: 901-495-2174; Fax: 901-525-6869; E-mail: john.schuetz{at}stjude.org.

Key Words: abc transporter • Mrp4 • thiopurine

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. [Cancer Res 2008;68(13):4983–9]