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
ISSN
1538-7445 (Electronic)
0008-5472 (Print)
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.
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 6:17
Last modification date
27/08/2023 7:01