Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5)

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.