PT  - JOURNAL ARTICLE
AU  - Yasumasa Gotoh
AU  - Hiroshi Suzuki
AU  - Setsuo Kinoshita
AU  - Tomoko Hirohashi
AU  - Yukio Kato
AU  - Yuichi Sugiyama
TI  - Involvement of an Organic Anion Transporter (Canalicular Multispecific Organic Anion Transporter/Multidrug Resistance-Associated Protein 2) in Gastrointestinal Secretion of Glutathione Conjugates in Rats
DP  - 2000 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 433--439
VI  - 292
IP  - 1
4099  - http://jpet.aspetjournals.org/content/292/1/433.short
4100  - http://jpet.aspetjournals.org/content/292/1/433.full
SO  - J Pharmacol Exp Ther2000 Jan 01; 292
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics