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 Res
Author(s)
Krishnamurthy P., Schwab M., Takenaka K., Nachagari D., Morgan J., Leslie M., Du W., Boyd K., Cheok M., Nakauchi H., Marzolini C., Kim R. B., Poonkuzhali B., Schuetz E., Evans W., Relling M., Schuetz J. D.
ISSN
1538-7445 (Electronic)
0008-5472 (Print)
ISSN-L
0008-5472
Publication state
Published
Issued date
2008
Peer-reviewed
Oui
Volume
68
Number
13
Pages
4983-9
Language
english
Notes
Krishnamurthy, Partha
Schwab, Matthias
Takenaka, Kazumasa
Nachagari, Deepa
Morgan, Jessica
Leslie, Mark
Du, Weinan
Boyd, Kelli
Cheok, Meyling
Nakauchi, Hiromitsu
Marzolini, Catia
Kim, Richard B
Poonkuzhali, Balasubramanian
Schuetz, Erin
Evans, William
Relling, Mary
Schuetz, John D
eng
P01 GM031304/GM/NIGMS NIH HHS/
U01 GM061393/GM/NIGMS NIH HHS/
R56 GM060904-09/GM/NIGMS NIH HHS/
R01 GM060904/GM/NIGMS NIH HHS/
CA21765/CA/NCI NIH HHS/
GM60904/GM/NIGMS NIH HHS/
U01 GM61393/GM/NIGMS NIH HHS/
CA23097/CA/NCI NIH HHS/
GM31304/GM/NIGMS NIH HHS/
R01 ES005851-15/ES/NIEHS NIH HHS/
P01 GM031304-24/GM/NIGMS NIH HHS/
R01 ES005851/ES/NIEHS NIH HHS/
P30 CA021765-30/CA/NCI NIH HHS/
R56 GM060904/GM/NIGMS NIH HHS/
U01GM61374/GM/NIGMS NIH HHS/
P30 CA021765/CA/NCI NIH HHS/
U01 GM061374/GM/NIGMS NIH HHS/
U01 GM061393-090009/GM/NIGMS NIH HHS/
R01 CA194206/CA/NCI NIH HHS/
ESO58571/PHS HHS/
U01 GM061374-07/GM/NIGMS NIH HHS/
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Cancer Res. 2008 Jul 1;68(13):4983-9. doi: 10.1158/0008-5472.CAN-07-6790.
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/*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
Pubmed
Create date
25/08/2023 5:17
Last modification date
27/08/2023 6:01
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