Wielinga P R, Reid G, Challa E E, van der Heijden I, van Deemter L, de Haas M, Mol C, Kuil A J, Groeneveld E, Schuetz J D, Brouwer C, De Abreu R A, Wijnholds J, Beijnen J H, Borst P
Division of Molecular Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Mol Pharmacol. 2002 Dec;62(6):1321-31. doi: 10.1124/mol.62.6.1321.
Mercaptopurines have been used as anticancer agents for more than 40 years, and most acute lymphoblastic leukemias are treated with 6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two related multidrug resistance proteins MRP4 and MRP5 has been shown to confer some resistance against mercaptopurines, which has been attributed to extrusion of mercaptopurine metabolites by these transporters. We have analyzed the mercaptopurine metabolites formed in human embryonic kidney cells and determined which metabolites are extruded by MRP4 and MRP5. Incubation with 6MP led to the formation of thioinosine and thioxanthosine metabolites and we found that thio-IMP was transported by both MRP4 and MRP5; MRP5 showed the highest transport rate. In contrast, only MRP5 transported thioxanthosine monophosphate (tXMP). During incubation with TG, the monophosphorylated form of thioguanosine was transported by both MRP4 and MRP5; the highest transport rate was for MRP4. Similarly, only 6-methyl-thio-IMP was formed during incubation with 6-methyl mercaptopurine riboside. This compound was a substrate for both MRP4 and MRP5; MRP4 showed the highest transport rate. Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail.
巯嘌呤作为抗癌药物已使用了40多年，大多数急性淋巴细胞白血病都用6-巯基嘌呤（6MP）或6-硫鸟嘌呤（TG）进行治疗。已表明两种相关的多药耐药蛋白MRP4和MRP5的过表达赋予了对巯嘌呤的一定抗性，这归因于这些转运蛋白对巯嘌呤代谢物的外排。我们分析了人胚肾细胞中形成的巯嘌呤代谢物，并确定了哪些代谢物被MRP4和MRP5外排。用6MP孵育导致硫代次黄苷和硫代黄苷代谢物的形成，我们发现硫代肌苷一磷酸（thio-IMP）可被MRP4和MRP5转运；MRP5显示出最高的转运速率。相比之下，只有MRP5转运硫代黄苷单磷酸（tXMP）。在用TG孵育期间，硫代鸟苷的单磷酸化形式可被MRP4和MRP5转运；MRP4的转运速率最高。同样，在用6-甲基巯基嘌呤核苷孵育期间只形成了6-甲基硫代肌苷一磷酸。该化合物是MRP4和MRP5的底物；MRP4显示出最高的转运速率。我们的结果表明，巯嘌呤治疗疗效中重要的所有主要硫嘌呤单磷酸都可被MRP4和MRP5转运，尽管这两种转运蛋白的底物特异性在细节上有所不同。
