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Am J Physiol Gastrointest Liver Physiol 278: G438-G446, 2000;
0193-1857/00 $5.00
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Vol. 278, Issue 3, G438-G446, March 2000

Characterization of inducible nature of MRP3 in rat liver

Kotaro Ogawa1, Hiroshi Suzuki1,5, Tomoko Hirohashi1,5, Toshihisa Ishikawa2, Peter J. Meier3, Kenji Hirose4, Toshifumi Akizawa4, Masanori Yoshioka4, and Yuichi Sugiyama1,5

1 Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; 2 Department of Experimental Pediatrics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; 3 Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland; 4 Faculty of Pharmaceutical Sciences, Setsunan University, Nagao-toge-machi, Hirakata, 573-01, Japan; and 5 Core Research for Evolutional Sciences and Technology, Japan Science and Technology, Tokyo 113-0033, Japan

We found previously that expression of multidrug resistance-associated protein (MRP) 3 is induced in a mutant rat strain (Eisai hyperbilirubinemic rats) whose canalicular multispecific organic anion transporter (cMOAT/MRP2) function is hereditarily defective and in normal Sprague-Dawley (SD) rats after ligation of the common bile duct. In the present study, the inducible nature of MRP3 was examined, using Northern and Western blot analyses, in comparison with that of other secondary active [Na+-taurocholic acid cotransporting polypeptide (Ntcp), organic anion transporting polypeptide 1 (oatp1), and organic cation transporter (OCT1)] and primary active [P-glycoprotein (P-gp), cMOAT/MRP2, and MRP6] transporters. alpha -Naphthylisothiocyanate treatment and common bile duct ligation induced expression of P-gp and MRP3, whereas expression of Ntcp, oatp1, and OCT1 was reduced by the same treatment. Although expression of MRP3 was also induced by administration of phenobarbital, that of cMOAT/MRP2, MRP1, and MRP6 was not affected by any of these treatments. Moreover, the mRNA level of MRP3, but not that of P-gp, was increased in SD rats after administration of bilirubin and in Gunn rats whose hepatic bilirubin concentration is elevated because of a defect in the expression of UDP-glucuronosyl transferase. However, the MRP3 protein level was not affected by bilirubin administration. Although the increased MRP3 mRNA level was associated with the increased concentration of bilirubin and/or its glucuronides in mutant rats and in SD rats that had undergone common bile duct ligation or alpha -naphthylisothiocyanate treatment, we must assume that factor(s) other than these physiological substances are also involved in the increased protein level of MRP3.

induction; multidrug resistance-associated protein; canalicular multispecific organic anion transporter; cholestasis; bilirubin glucuronide


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