Ritter Christoph A, Jedlitschky Gabriele, Meyer zu Schwabedissen Henriette, Grube Markus, Köck Kathleen, Kroemer Heyo K
Department of Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
Drug Metab Rev. 2005;37(1):253-78. doi: 10.1081/dmr-200047984.
Like other members of the multidrug resistance protein (MRP)/ABCC subfamily of ATP-binding cassette transporters, MRP4 (ABCC4) and MRP5 (ABCC5) are organic anion transporters. They have, however, the outstanding ability to transport nucleotides and nucleotide analogs. In vitro experiments using drug-selected or -transfected cells indicated that these transport proteins, when overexpressed, can lower the intracellular concentration of nucleoside/nucleotide analogs, such as the antiviral compounds PMEA (9-(2-phosphonylmethoxyethyl)adenine) or ganciclovir, and of anticancer nucleobase analogs, such as 6-mercaptopurine, after their conversion into the respective nucleotides. This may lead to an impaired ability of these compounds to inhibit virus replication or cell proliferation. It remains to be tested whether antiviral or anticancer chemotherapy based on nucleobase, nucleoside, or nucleotide precursors can be modulated by inhibition of MRP4 and MRP5. MRP4 also seems to be able to mediate the transport of conjugated steroids, prostaglandins, and glutathione. Furthermore, cyclic nucleotides (cyclic adenosine monophosphate and cyclic guanine monophosphate) are exported from cells by MRP4 and MRP5. This may modulate the intracellular concentration of these important mediators, besides the action of phosphodiesterases, as well as provide extracellular nucleotides for a possible paracrine action. In this line, tissue distribution and subcellular localization of MRP4 and MRP5 specifically in smooth muscle cells (MRP5), platelet-dense granules (MRP4), and nervous cells (MRP4 and MRP5), besides the capillary endothelium, point not only to a possible function of these transporters as exporters in cellular defense, but also to a physiological function in signaling processes.
与ATP结合盒转运体的多药耐药蛋白（MRP）/ABCC亚家族的其他成员一样，MRP4（ABCC4）和MRP5（ABCC5）是有机阴离子转运体。然而，它们具有转运核苷酸和核苷酸类似物的卓越能力。使用药物筛选或转染细胞进行的体外实验表明，这些转运蛋白在过表达时，可降低核苷/核苷酸类似物的细胞内浓度，例如抗病毒化合物PMEA（9-(2-膦酰甲氧基乙基)腺嘌呤）或更昔洛韦，以及抗癌核苷类似物，如6-巯基嘌呤，这些类似物在转化为各自的核苷酸后。这可能导致这些化合物抑制病毒复制或细胞增殖的能力受损。基于核苷、核苷或核苷酸前体的抗病毒或抗癌化疗是否可通过抑制MRP4和MRP5来调节，仍有待测试。MRP4似乎还能够介导结合型类固醇、前列腺素和谷胱甘肽的转运。此外，环核苷酸（环磷酸腺苷和环磷酸鸟苷）可由MRP4和MRP从细胞中输出。这除了磷酸二酯酶的作用外，可能调节这些重要介质的细胞内浓度，并为可能的旁分泌作用提供细胞外核苷酸。在这方面，MRP4和MRP5在平滑肌细胞（MRP5）、血小板致密颗粒（MRP4）和神经细胞（MRP4和MRP5）以及毛细血管内皮中的组织分布和亚细胞定位，不仅表明这些转运体作为细胞防御中的输出器可能具有的功能，还表明其在信号传导过程中的生理功能。
