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Functional Analysis of Mouse and Monkey Multidrug Resistance-Associated Protein 2 (Mrp2)

Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University Chiba, Japan (M.N., R.H., T.H.); and Department of Pharmacy, the University of Tokyo Hospital, the University of Tokyo, Tokyo, Japan (K.I.)

We investigated the intrinsic transport activity of mouse and monkey Mrp2 and compared it with that of rat and dog Mrp2 reported previously. Mrp2 cDNAs were isolated from BALB/c and Macaca fascicularis liver, respectively, and vesicle transport studies were performed using recombinant Mrp2s expressed in insect Sf9 cells. ATP-dependent transport of [³H]leukotriene C₄ (LTC₄), ³[H]17ß-estradiol 17-(ß-D-glucuronide) (E₂17ßG), [³H]bromosulfophthalein (BSP), and [³H]cholecystokinin octapeptide (CCK-8) were readily detected for all Mrp2s. A species difference in the intrinsic transport activity was apparent for LTC₄ (monkey > mouse, dog > rat) and BSP (rat, dog, monkey > mouse). In addition to the difference in the transport activity, complex kinetic profiles were also evident in CCK-8, where a cooperative transport site was observed. Moreover, the transport of [³H]E₂17ßG by mouse and monkey Mrp2 was quite different from that of rat and dog Mrp2 in that 1) there was practically only nonsaturable uptake for [³H]E₂17ßG and 2) 4-methylumbelliferon glucuronide (Mrp2 modulator) showed a concentration-dependent stimulatory effect on the transport of [³H]E₂17ßG in mouse and monkey Mrp2, whereas rat and dog transport activity was inhibited by the modulator. In conclusion, although the substrate specificity is similar, the intrinsic transport activity differs from one species to another. This is due not only to the difference in the K_m and V_max values, but also the qualitatively different mode of substrate and modulator recognition exhibited by different species.

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