title: 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.affiliation: Department of Pharmaceutical Sciences and Animal Resource Center, St Jude Children's Research Hospital, Memphis, Tenessee 38105, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Takenaka
authors.forename: Deepa
authors.initials: D
authors.lastname: Nachagari
authors.forename: Jessica
authors.initials: J
authors.lastname: Morgan
authors.forename: Mark
authors.initials: M
authors.lastname: Leslie
authors.forename: Weinan
authors.initials: W
authors.lastname: Du
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.forename: Meyling
authors.initials: M
authors.lastname: Cheok
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Catia
authors.initials: C
authors.lastname: Marzolini
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Poonkuzhali
authors.forename: Erin
authors.initials: E
authors.lastname: Schuetz
authors.forename: William
authors.initials: W
authors.lastname: Evans
authors.forename: Mary
authors.initials: M
authors.lastname: Relling
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
mesh_terms: D000483:Alleles; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006402:Hematologic Diseases / Q000139:chemically induced* / Q000401:mortality; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015122:Mercaptopurine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011687:Purines / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D013438:Sulfhydryl Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D016019:Survival Analysis; D014018:Tissue Distribution
chemical_list: D026901:Membrane Transport Proteins; D015122:Mercaptopurine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011687:Purines; D013438:Sulfhydryl Compounds; C073492:ABCC4 protein, human