|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
13
|
|
pubmed:dateCreated |
2008-7-2
|
|
pubmed:abstractText |
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.
|
|
pubmed:grant |
http://linkedlifedata.com/resource/pubmed/grant/CA21765,
http://linkedlifedata.com/resource/pubmed/grant/CA23097,
http://linkedlifedata.com/resource/pubmed/grant/ESO58571,
http://linkedlifedata.com/resource/pubmed/grant/GM31304,
http://linkedlifedata.com/resource/pubmed/grant/GM60904,
http://linkedlifedata.com/resource/pubmed/grant/P01 GM031304-24,
http://linkedlifedata.com/resource/pubmed/grant/P30 CA021765-30,
http://linkedlifedata.com/resource/pubmed/grant/R01 ES005851-15,
http://linkedlifedata.com/resource/pubmed/grant/R56 GM060904-09,
http://linkedlifedata.com/resource/pubmed/grant/U01 GM061374-07,
http://linkedlifedata.com/resource/pubmed/grant/U01 GM061393-090009,
http://linkedlifedata.com/resource/pubmed/grant/U01 GM61393,
http://linkedlifedata.com/resource/pubmed/grant/U01GM61374
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Jul
|
|
pubmed:issn |
1538-7445
|
|
pubmed:author |
pubmed-author:BalasubramanianPoonkuzhaliP,
pubmed-author:BoydKelliK,
pubmed-author:CheokMeylingM,
pubmed-author:EvansWilliamW,
pubmed-author:KimRichard BRB,
pubmed-author:KrishnamurthyParthaP,
pubmed-author:LeslieMarkM,
pubmed-author:MarzoliniCatiaC,
pubmed-author:MorganJessicaJ,
pubmed-author:NachagariDeepaD,
pubmed-author:NakauchiHiromitsuH,
pubmed-author:RellingMaryM,
pubmed-author:SchuetzErinE,
pubmed-author:SchuetzJohn DJD,
pubmed-author:SchwabMatthiasM,
pubmed-author:TakenakaKazumasaK,
pubmed-author:WeilerOO
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
1
|
|
pubmed:volume |
68
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
4983-9
|
|
pubmed:dateRevised |
2011-8-1
|
|
pubmed:meshHeading |
pubmed-meshheading:18593894-6-Mercaptopurine,
pubmed-meshheading:18593894-Alleles,
pubmed-meshheading:18593894-Animals,
pubmed-meshheading:18593894-Cell Membrane,
pubmed-meshheading:18593894-Cells, Cultured,
pubmed-meshheading:18593894-Cytoprotection,
pubmed-meshheading:18593894-Drug Resistance, Neoplasm,
pubmed-meshheading:18593894-Hematologic Diseases,
pubmed-meshheading:18593894-Hematopoiesis,
pubmed-meshheading:18593894-Humans,
pubmed-meshheading:18593894-Leukemia, Myeloid, Acute,
pubmed-meshheading:18593894-Membrane Transport Proteins,
pubmed-meshheading:18593894-Mice,
pubmed-meshheading:18593894-Mice, Knockout,
pubmed-meshheading:18593894-Models, Biological,
pubmed-meshheading:18593894-Multidrug Resistance-Associated Proteins,
pubmed-meshheading:18593894-Polymorphism, Single Nucleotide,
pubmed-meshheading:18593894-Purines,
pubmed-meshheading:18593894-Sulfhydryl Compounds,
pubmed-meshheading:18593894-Survival Analysis,
pubmed-meshheading:18593894-Tissue Distribution
|
|
pubmed:year |
2008
|
|
pubmed:articleTitle |
Transporter-mediated protection against thiopurine-induced hematopoietic toxicity.
|
|
pubmed:affiliation |
Department of Pharmaceutical Sciences and Animal Resource Center, St Jude Children's Research Hospital, Memphis, Tenessee 38105, USA.
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|
