期刊
CANCER RESEARCH
卷 68, 期 13, 页码 4983-4989出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-6790
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- NCI NIH HHS [R01 CA194206, P30 CA021765, CA21765, P30 CA021765-30, CA23097] Funding Source: Medline
- NIEHS NIH HHS [R01 ES005851-15, R01 ES005851] Funding Source: Medline
- NIGMS NIH HHS [R56 GM060904-09, U01 GM061393, P01 GM031304, U01 GM061374-07, R01 GM060904, GM60904, U01 GM61393, GM31304, P01 GM031304-24, R56 GM060904, U01GM61374, U01 GM061374, U01 GM061393-090009] Funding Source: Medline
- PHS HHS [ESO58571] Funding Source: Medline
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.
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