Transporter-mediated protection against thiopurine-induced hematopoietic toxicity.
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.
Krishnamurthy
Partha
P
Department of Pharmaceutical Sciences and Animal Resource Center, St Jude Children's Research Hospital, Memphis, Tenessee 38105, USA.
Schwab
Matthias
M
Takenaka
Kazumasa
K
Nachagari
Deepa
D
Morgan
Jessica
J
Leslie
Mark
M
Du
Weinan
W
Boyd
Kelli
K
Cheok
Meyling
M
Nakauchi
Hiromitsu
H
Marzolini
Catia
C
Kim
Richard B
RB
Poonkuzhali
Balasubramanian
B
Schuetz
Erin
E
Evans
William
W
Relling
Mary
M
Schuetz
John D
JD
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
D026901:Membrane Transport Proteins; D015122:Mercaptopurine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011687:Purines; D013438:Sulfhydryl Compounds; C073492:ABCC4 protein, human