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 K_m andV_max 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(K_i(app), 1.5 μM), glycolithocholate 3-sulfate (K_i(app), 34.2 μM) and MK571 (K_i(app), 28.5 μM), and lipophilic agents such as cyclosporine A (K_i(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.