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Molecular Pharmacology

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Research ArticleArticle

Hepatic Expression of Multidrug Resistance-Associated Protein-Like Proteins Maintained in Eisai Hyperbilirubinemic Rats

Tomoko Hirohashi, Hiroshi Suzuki, Kousei Ito, Kotaro Ogawa, Kazuhiko Kume, Takao Shimizu and Yuichi Sugiyama
Molecular Pharmacology June 1998, 53 (6) 1068-1075;
Tomoko Hirohashi
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Hiroshi Suzuki
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Kousei Ito
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Kotaro Ogawa
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Kazuhiko Kume
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Takao Shimizu
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Yuichi Sugiyama
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Abstract

The biliary excretion of several organic anions is mediated by the canalicular multispecific organic anion transporter (cMOAT), which is hereditarily defective in mutant rats such as Eisai hyperbilirubinemic rats (EHBR). In addition, using a kinetic study with isolated canalicular membrane vesicles, we recently suggested the presence of ATP-dependent organic anion transporter(s) other than cMOAT in EHBR [Pharm Res (NY) 12:1746–1755 (1995);J Pharmacol Exp Ther 282:866–872 (1997)]. The aim of this study is to provide a molecular basis for the presence of multiplicity in the biliary excretion of organic anions in rats. Based on the homology with human multidrug resistance-associated protein (hMRP), two cDNA fragments encoding the carboxyl-terminal ATP-binding cassette region were amplified by reverse transcription-polymerase chain reaction from EHBR liver. These fragments exhibited approximately 70% amino acid identity with hMRP and rat cMOAT;, therefore, they were designated MRP-like proteins (MLP-1 and MLP-2). The cloned full length cDNA of MLP-1 and -2 from the Sprague-Dawley (SD) rat liver and colon cDNA library was composed of 1502 and 1523 amino acids, respectively, had the characteristics of ATP-binding cassette transporters, and exhibited homology with hMRP and rat cMOAT. Northern blot analysis indicated that MLP-1 is expressed predominantly in the liver in both SD rats and EHBR, whereas hepatic expression of MLP-2 was observed only in EHBR. In addition, MLP-2 was markedly induced by ligation of the bile duct in SD rat liver. In both SD rats and EHBR, MLP-2 was expressed predominantly in the duodenum, jejunum, and colon. These findings suggest that MLP-1 and MLP-2 might be novel members of the MRP family responsible for the excretion of organic anions from these epithelial cells, and that MLP-2 is an inducible one.

Footnotes

  • Send reprint requests to: Yuichi Sugiyama, Ph.D., Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail:bxg05433{at}niftyserve.or.jp

  • This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan, and the Core Research for Evolutional Sciences and Tecnology of Japan Sciences and Technology Corporation.

  • ↵1 The sequences reported in this paper have been submitted to the GenBank with the accession numbers AB010466 (MLP-1) and AB010467(MLP-2).

  • Abbreviations:
    cMOAT
    canalicular multispecific organic anion transporter
    hMRP
    human multidrug resistance-associated protein
    MLP
    multidrug resistance-associated protein-like protein
    ABC
    ATP-binding cassette
    DNP-SG
    S-(2,4-dinitrophenyl) glutathione
    E3040
    6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole
    CMVs
    canalicular membrane vesicles
    SD
    Sprague-Dawley
    EHBR
    Eisai hyperbilirubinemic rats
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    bp
    base pair(s)
    kb
    kilobase pair(s)
    SSC
    standard saline citrate
    SDS
    sodium dodecyl sulfate
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    • Received December 9, 1997.
    • Accepted March 10, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (6)
Molecular Pharmacology
Vol. 53, Issue 6
1 Jun 1998
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Research ArticleArticle

Hepatic Expression of Multidrug Resistance-Associated Protein-Like Proteins Maintained in Eisai Hyperbilirubinemic Rats

Tomoko Hirohashi, Hiroshi Suzuki, Kousei Ito, Kotaro Ogawa, Kazuhiko Kume, Takao Shimizu and Yuichi Sugiyama
Molecular Pharmacology June 1, 1998, 53 (6) 1068-1075;

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Research ArticleArticle

Hepatic Expression of Multidrug Resistance-Associated Protein-Like Proteins Maintained in Eisai Hyperbilirubinemic Rats

Tomoko Hirohashi, Hiroshi Suzuki, Kousei Ito, Kotaro Ogawa, Kazuhiko Kume, Takao Shimizu and Yuichi Sugiyama
Molecular Pharmacology June 1, 1998, 53 (6) 1068-1075;
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