Involvement of an organic anion transporter (canalicular multispecific organic anion transporter/multidrug resistance-associated protein 2) in gastrointestinal secretion of glutathione conjugates in rats.
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 micromol/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.
Gotoh
Y
Y
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
Suzuki
H
H
Kinoshita
S
S
Hirohashi
T
T
Kato
Y
Y
Sugiyama
Y
Y
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D027321:Anion Transport Proteins; D001659:Biliary Tract / Q000378:metabolism; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D004064:Digestive System / Q000378:metabolism*; D004137:Dinitrochlorobenzene / Q000097:blood; D005978:Glutathione / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D006933:Hyperbilirubinemia, Hereditary / Q000378:metabolism*; D066298:In Vitro Techniques; D007419:Intestinal Secretions; D007583:Jejunum / Q000737:chemistry; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D018528:ATP-Binding Cassette Transporters; D027321:Anion Transport Proteins; D002352:Carrier Proteins; D004137:Dinitrochlorobenzene; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C030190:S-(2,4-dinitrophenyl)glutathione