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Vol. 292, Issue 1, 265-270, January 2000
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Hongo, Bunkyo-ku, Tokyo (T.H., H.S., X.-Y.C, Y.S.); and Faculty
of Pharmaceutical Sciences, Kanazawa University, Takaramachi, Kanazawa
(I.T., A.T.), Japan
Several organic anions are actively extruded from intestinal epithelial
cells into the lumen and vascular sides. To examine the role of
the multidrug resistance-associated protein (MRP) family in the
intestinal efflux of organic anions, the function and expression of
these proteins were investigated with Caco-2, a human adenocarcinoma
cell line that retains many of the characteristics of normal
enterocytes.
[3H]2,4-Dinitrophenyl-S-glutathione
(DNP-SG) and [3H]17
-estradiol
17--D-glucuronide (E217G), typical
substrates for MRP1 and cMOAT (canalicular multispecific organic anion
transporter)/MRP2, were taken up into brush-border membrane vesicles
(BBMVs) from Caco-2 in an ATP-dependent manner, with
Km values of 16.9 ± 7.2 and 9.4 ± 1.2 µM, respectively. The uptake of [3H]DNP-SG into
BBMVs was osmotically sensitive and stimulated to some extent by other
nucleotide triphosphates (GTP, CTP, and UTP) but not by ADP or AMP. An
ATPase inhibitor, vanadate, inhibited the ATP-dependent uptake of
[3H]DNP-SG to some extent. Reverse-transcriptase
polymerase chain reaction resulted in the amplification of MRP1, MRP3,
and MRP5. Northern blot analysis indicated extensive expression of
cMOAT/MRP2 and MRP3 and only minimal expression of MRP1 and MRP5.
Although cMOAT/MRP2 was continuously expressed throughout the culture
period, MRP3 was not expressed immediately after the confluent state
was reached. Collectively, the presence of ATP-dependent transport systems for DNP-SG and E217G was demonstrated in Caco-2
cells. Because cMOAT/MRP2 and MRP3 may be expressed on brush-border and basolateral membranes in epithelial cells, respectively, the transport activity associated with BBMVs may result from the function of cMOAT/MRP2.
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