Abstract
Multidrug resistance protein 2 (MRP2) is a multispecific organic anion transporter expressed at important pharmacological barriers, including the canalicular membrane of hepatocytes. At this location it is involved in the elimination of both endogenous and exogenous waste products, mostly as conjugates, to the bile. Estradiol-17β-d-glucuronide (E217βG), a widely studied endogenous substrate of MRP2, was shown earlier to recognize two binding sites of the transporter in vesicular transport assays. MRP2 modulators (substrates and nonsubstrates) potentiate the transport of E217βG by MRP2. We correlated data obtained from studies of different complexities and investigated the species-specific differences between rat and human MRP2-mediated transport. We used vesicular transport assays, sandwich-cultured primary hepatocytes, and in vivo biliary efflux in rats. Our results demonstrate that the rat Mrp2 transporter, unlike the human MRP2, transports E217βG according to Michaelis-Menten type kinetics. Nevertheless, in the presence of modulator drugs E217βG transport mediated by the rat transporter also shows cooperative kinetics as potentiation of E217βG transport was observed in the vesicular transport assay. We also demonstrated that the potentiation exists both in rat and in human hepatocytes and in vivo in rats.
Footnotes
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This work was supported in part by the Hungarian Office for Research and Technology [Grants OTKA T 043141, GVOP-2004-3.3.2.-2004-04-0001/3.0, GVOP-3.1.1.-2004-05-0506/3.0]; Emberi Erőforrás Fejlesztés (Human Resources Development)-Munka 00034/2003; and the European Union [Grants FP6-NoE 005137, LSBH-CT-2006-518246, LSHB-CT-2006-037499].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.023895.
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ABBREVIATIONS: MRP2/Mrp2 (ABCC2, cMOAT), multidrug resistance protein 2; E217βG, estradiol-17β-d-glucuronide; Sf9, Spodoptera frugiperda ovarian; MOPS, 4-morpholinepropanesulfonic acid; HBSS, Hanks' balanced salt solution.
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↵1 K.H.-S. and H.G. contributed equally to this work.
- Received August 13, 2008.
- Accepted December 31, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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