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Vol. 292, Issue 1, 433-439, January 2000
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Hongo, Bunkyo-ku, Tokyo (Y.G., H.S., S.K., T.H., Y.K., Y.S.);
and Core Research for Evolutional Science and Technology, Japan Science
and Technology Corporation, Kawaguchi City, Japan (H.S., T.H.,
Y.K.,Y.S.)
We investigated the role of cMOAT/MRP2 (canalicular multispecific
organic anion transporter/multidrug resistance-associated protein 2) in
the intestinal secretion of organic anions by comparing the behavior in
Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rat (EHBR) whose
cMOAT/MRP2 is hereditarily defective. After i.v. administration of
1-chloro-2,4-dinitrobenzene (30 µmol/kg), the biliary and intestinal
excretion of its glutathione conjugate 2,4-dinitrophenyl-S-glutathione (DNP-SG), a substrate
for cMOAT/MRP2, was significantly reduced in EHBR compared with SD
rats. This result also was confirmed by Ussing chamber studies; DNP-SG
showed 1.5-fold greater serosal-to-mucosal flux compared with the
mucosal-to-serosal flux in SD rats, whereas a similar flux was observed
in both directions in EHBR. In addition, metabolic inhibitors reduced
the preferential serosal-to-mucosal flux of DNP-SG in SD rats. In
everted sac studies, intestinal secretion clearance, defined as the
efflux rate of DNP-SG into the mucosal side divided by the area under
the curve on the serosal side, was significantly lower in the jejunum
of EHBR than that in SD rats. Northern blot analyses demonstrated the
highest mRNA level of cMOAT/MRP2 in the jejunum, which is in good
agreement with the results of the everted sac studies. These results
suggest that cMOAT/MRP2 is involved in the secretion of organic anions
in the small intestine.
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