Species-dependent transport and modulation properties of human and mouse multidrug resistance protein 2 (MRP2/Mrp2, ABCC2/Abcc2).
Multidrug resistance protein 2 (MRP2/Mrp2) is a transporter that can influence the absorption, distribution, and elimination of many drugs. Mrp2 knockout mice are being used to study Mrp2 functions in vivo, including pharmacokinetics of drugs. To assess possible species-specific differences between human MRP2 and mouse Mrp2, we generated polarized cell lines expressing mouse Mrp2 and used these to investigate transport of clinically important agents. We also tested the ability of other drugs to modulate MRP2/Mrp2-mediated transport, a phenomenon that can lead to drug-drug interactions. In MDCK cells stably expressing human MRP2 or mouse Mrp2, saquinavir and docetaxel were more efficiently transported by mouse Mrp2, whereas vinblastine was transported better by human MRP2. MRP2/Mrp2-mediated transepithelial transport of several drugs could be stimulated by probenecid and sulfanitran, but stimulation was often more pronounced for human MRP2 than for mouse Mrp2. Interestingly, for some drugs the MRP2 modulator sulfinpyrazone had opposite effects on both transporters, stimulating human MRP2 and inhibiting mouse Mrp2 activity. In vesicular transport studies, transport of estradiol-17beta-glucuronide by mouse Mrp2 showed homotropic cooperativity, as previously described for human MRP2. The MRP2 modulators again showed differential effects on estradiol-17beta-glucuronide transport, most notably with sulfinpyrazone stimulating human MRP2 and profoundly inhibiting mouse Mrp2 activity. In conclusion, although human and mouse MRP2/Mrp2 have largely overlapping substrate specificities, there are important species differences in the transport efficiency of MRP2 substrates and in the modulation of transport by other compounds. These differences should be taken into account when results obtained in mice are extrapolated to humans.
Zimmermann
Christian
C
Division of Experimental Therapy, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
van de Wetering
Koen
K
van de Steeg
Evita
E
Wagenaar
Els
E
Vens
Conchita
C
Schinkel
Alfred H
AH
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007313:Insecta; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D013045:Species Specificity; D013379:Substrate Specificity
D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D004364:Pharmaceutical Preparations; C000715087:ABCC2 protein, human