Abstract
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.
Footnotes
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Send reprint requests to: Dr. Yuichi Sugiyama, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail:sugiyama{at}seizai.f.u-tokyo.ac.jp
- Abbreviations:
- mdr
- multidrug resistant
- P-gp
- P-glycoprotein
- cMOAT
- canalicular multispecific organic anion transporter
- MRP
- multidrug resistance-associated protein
- TR−
- transport deficient rats
- EHBR
- Eisai hyperbilirubinemic rats
- CDNB
- 1-chloro-2,4-dinitrobenzene
- FDNB
- 1-fluoro-2,4-dinitrobenzene
- SD rats
- Sprague-Dawley rats
- DNP-SG
- 2,4-dinitrophenyl-S-glutathione
- DNP-CG
- 2,4-dinitrophenyl-S-cysteinylglycine
- DNP-Nac
- 2,4-dinitrophenyl-N-acetylcysteine
- DNP-Cys
- 2,4-dinitrophenyl-S-cysteine
- AUC
- area under the curve
- G3PDH
- glyceraldehyde 3-phosphate dehydrogenase
- LTC4
- leukotriene C4
- NAcLTE4
- N-acetyl leukotriene E4
- Received June 14, 1999.
- Accepted October 4, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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