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Vol. 53, Issue 6, 1062-1067, June 1998
Departments of
Pharmacology (R.A.M.H. van A., F.G.M.R.),
Biochemistry (J.B.K.), and
Cell Physiology (M.A. van K., P.M.T.D.,
C.H. van O.), University of Nijmegen, 6500 HB Nijmegen, The Netherlands
The multidrug resistance-associated protein Mrp2 is expressed in liver,
kidney, and small intestine and mediates ATP-dependent transport of
conjugated organic anions across the apical membrane of epithelial
cells. We recently cloned a rabbit cDNA encoding a protein that on
basis of highest amino acid homology and tissue distribution was
considered to be the rabbit homolog of rat Mrp2. To investigate whether
rabbit Mrp2 mediates ATP-dependent transport similar to rat Mrp2, we
expressed rabbit Mrp2 in Spodoptera frugiperda (Sf9)
cells using recombinant baculovirus. Mrp2 was expressed as an
underglycosylated protein in Sf9 cells and to a higher level compared
with rabbit liver and renal proximal tubules. Both
17
-estradiol-17--D-glucuronide ([3H]E217G, 50 nM) and
[3H]leukotriene C4 (3 nM) were
taken up by Sf9-Mrp2 membrane vesicles in an ATP-dependent fashion.
Uptake of [3H]E217G was dependent on the
osmolarity of the medium and saturable for ATP
(Km = 623 µM). Leukotriene
C4, MK571, phenolphthalein glucuronide, and
fluorescein-methotrexate were good inhibitors of
[3H]E217G transport. The inhibitory
potency of cyclosporin A and methotrexate was moderate, whereas
fluorescein, 
-naphthyl--D-glucuronide, and
p-nitrophenyl--D-glucuronide did not
inhibit transport. In conclusion, we show direct ATP-dependent
transport by recombinant rabbit Mrp2 and provide new data on Mrp2
inhibitor specificity.
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