Transporter-mediated protection against thiopurine-induced hematopoietic toxicity.
Details
Serval ID
serval:BIB_B46C08CD3C0B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Transporter-mediated protection against thiopurine-induced hematopoietic toxicity.
Journal
Cancer research
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Publication state
Published
Issued date
01/07/2008
Peer-reviewed
Oui
Volume
68
Number
13
Pages
4983-4989
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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.
Keywords
Alleles, Animals, Cell Membrane/metabolism, Cells, Cultured, Cytoprotection/drug effects, Cytoprotection/genetics, Drug Resistance, Neoplasm/genetics, Hematologic Diseases/chemically induced, Hematologic Diseases/mortality, Hematopoiesis/drug effects, Humans, Leukemia, Myeloid, Acute/drug therapy, Leukemia, Myeloid, Acute/genetics, Membrane Transport Proteins/genetics, Membrane Transport Proteins/metabolism, Membrane Transport Proteins/physiology, Mercaptopurine/adverse effects, Mercaptopurine/pharmacology, Mercaptopurine/therapeutic use, Mice, Mice, Knockout, Models, Biological, Multidrug Resistance-Associated Proteins/genetics, Multidrug Resistance-Associated Proteins/metabolism, Multidrug Resistance-Associated Proteins/physiology, Polymorphism, Single Nucleotide/physiology, Purines/adverse effects, Purines/chemistry, Purines/therapeutic use, Sulfhydryl Compounds/adverse effects, Sulfhydryl Compounds/therapeutic use, Survival Analysis, Tissue Distribution
Pubmed
Web of science
Open Access
Yes
Create date
25/08/2023 6:17
Last modification date
05/08/2024 13:29