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Vol. 56, Issue 4, 714-719, October 1999
Departments of Pharmacology and Toxicology (R.A.M.H. van A.,
J.G.P.P., F.G.M.R.), Biochemistry (J.B.K.), and Cell Physiology (C.H.
van O.), University of Nijmegen, the Netherlands
The present study examined how the multidrug resistance protein
(MRP) 2, which is an ATP-dependent anionic conjugate
transporter, also mediates transport of the chemotherapeutic cationic
drug vinblastine (VBL). We show that ATP-dependent
[3H]VBL (0.2 µM) uptake into membrane vesicles from Sf9
cells infected with a baculovirus encoding rabbit Mrp2 (Sf9-Mrp2) was
similar to vesicles from mock-infected Sf9 cells (Sf9-mock) but could be stimulated by reduced glutathione (GSH) with a half-maximum stimulation of 1.9 ± 0.1 mM. At 5 mM GSH, initial ATP-dependent [3H]VBL uptake rates were saturable with an apparent
Km of 1.5 ± 0.3 µM. The inhibitory
effect of VBL on Mrp2-mediated ATP-dependent transport of the anionic
conjugate [3H]leukotriene C4 was
potentiated by increasing GSH concentrations. Membrane vesicles from
Sf9-Mrp2 cells exhibited a ~7-fold increase in initial GSH uptake
rates compared with membrane vesicles from Sf9-mock cells. Uptake of
[3H]GSH was osmotically sensitive, independent of ATP,
and was trans-inhibited by GSH. The anionic conjugates
estradiol-17
-D-glucuronide and leukotriene C4 cis-inhibited
[3H]GSH uptake but only in the presence of ATP.
Whereas ATP-dependent [3H]VBL uptake was stimulated by
GSH, VBL did not affect [3H]GSH uptake. Our results show
that GSH is required for Mrp2-mediated ATP-dependent VBL transport and
that Mrp2 transports GSH independent of VBL.
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