Characterization of the Transport Properties of Human Multidrug Resistance Protein 7 (MRP7, ABCC10)

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Abstract
Human multidrug resistance protein 7 (MRP7, ABCC10) is a recently described member of the C family of ATP binding cassette proteins (Cancer Lett162:181–191, 2001). However, neither its biochemical activity nor physiological functions have been determined. Here we report the results of investigations of the in vitro transport properties of MRP7 using membrane vesicles prepared from human embryonic kidney 293 cells transfected with MRP7 expression vector. It is shown that expression of MRP7 is specifically associated with the MgATP-dependent transport of 17β-estradiol-(17-β-d-glucuronide) (E217βG). E217βG transport was saturable, with Km andVmax values of 57.8 ± 15 μM and 53.1 ± 20 pmol/mg/min. By contrast, with E217βG, only modest enhancement of LTC4 transport was observed and transport of several other established substrates of MRP family transporters was not detectable to any extent. In accord with the notion that MRP7 has a bipartite substrate binding pocket composed of sites for anionic and lipophilic moieties, transport of E217βG was susceptible to competitive inhibition by both amphiphiles, such as leukotriene C4(Ki(app), 1.5 μM), glycolithocholate 3-sulfate (Ki(app), 34.2 μM) and MK571 (Ki(app), 28.5 μM), and lipophilic agents such as cyclosporine A (Ki(app), 14.4 μM). Of the inhibitors tested, LTC4 was the most potent, in agreement with the possibility that it is a substrate of the pump. The determination that MRP7 has the facility for mediating the transport of conjugates such as E217βG indicates that it is a lipophilic anion transporter involved in phase III (cellular extrusion) of detoxification.