The role of MRP family proteins in detoxification of xenobiotics in liver and intestine.

Among six members of MRP (multidrug resistance-associated protein) family proteins (MRPI-6), the function of MRP 1 and 2 has been well characterized. We have already cloned MRP3 as an inducible transporter in liver of mutant rats (EHBR) whose cMOAT is hereditarily defective. In this study, we examined the function of MRP3 using membrane vesicles prepared from rat MRP3-transfected LLC-PK1 cells. Although glucuronide conjugates are good substrates for MRP3, the substrate specificity of MRP3 differs from that of MRP1 and 2 in that glutathione conjugates are poor substrates for MRP3. In addition, MRP3 accepted both non-sulfated and sulfated bile salts as substrates. As MRP3 is highly expressed in intestinal tissues, the function and expression of MRP family proteins in intestinal tissues were investigated using Caco-2 cells as an in vitro model. DNP-SG and estradiol 17β-D-glucuronide were taken up by BBMV prepared from Caco-2 in an ATP-dependent manner. Northern blot analysis indicated high expression of human MRP2 and 3 and low expression of MRP1 and 5 in cultured Caco-2 cells.