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Vol. 63, Issue 2, 351-358, February 2003
Medical Sciences Division, Fox Chase Cancer Center, Philadelphia,
Pennsylvania
Human multidrug resistance protein 7 (MRP7, ABCC10) is a recently
described member of the C family of ATP binding cassette proteins
(Cancer Lett 162:181-191, 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 17
-estradiol-(17--D-glucuronide)
(E217G). E217G
transport was saturable, with Km and
Vmax values of 57.8 ± 15 µM
and 53.1 ± 20 pmol/mg/min. By contrast, with
E217G, 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 E217G 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 E217G indicates that it is a lipophilic anion transporter involved in phase III (cellular extrusion) of detoxification.
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