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First published on August 25, 2006; DOI: 10.1124/dmd.106.010991

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Received for publication May 8, 2006.
Revised August 23, 2006.
Accepted for publication August 24, 2006.

Functional analysis of Mouse and Monkey Multidrug resistance-associated protein 2 (Mrp2)

Mizuki Ninomiya 1, Kousei Ito 2, Remi Hiramatsu 1, Toshiharu Horie 1*

1 Chiba University 2 The University of Tokyo

* Address correspondence to: E-mail: horieto{at}p.chiba-u.ac.jp

Abstract

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]LTC4, [3H]E217{beta}G, [3H]BSP, and [3H]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]E217{beta}G by mouse and monkey Mrp2 was quite different from rat and dog Mrp2 in that, 1) there was practically only non-saturable uptake for [3H]E217{beta}G, 2) 4-methylumbelliferon glucuronide (Mrp2 modulator) showed a concentration-dependent stimulatory effect on the transport of [3H]E217{beta}G in mouse and monkey Mrp2, while rat and dog transport activity was inhibited by the modulator. In conclusion, while 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 Km and Vmax values, but also the qualitatively different mode of substrate and modulator recognition exhibited by different species.


Key words: ABC transporters, biliary excretion, hepatobiliary transport, MRP, organic anion transport


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