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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of the Transport Properties of Organic Anion Transporting Polypeptide 1 (oatp1) and Na+/Taurocholate Cotransporting Polypeptide (Ntcp): Comparative Studies on the Inhibitory Effect of their Possible Substrates in Hepatocytes and cDNA-Transfected COS-7 Cells

Hirokazu Kouzuki, Hiroshi Suzuki, Bruno Stieger, Peter J. Meier and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 2000, 292 (2) 505-511;
Hirokazu Kouzuki
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Hiroshi Suzuki
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Bruno Stieger
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Peter J. Meier
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Yuichi Sugiyama
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This article has a correction. Please see:

  • Correction to “Characterization of the Transport Properties of Organic Anion Transporting Polypeptide 1 (oatp1) and Na+/Taurocholate Cotransporting Polypeptide (Ntcp): Comparative Studies on the Inhibitory Effect of Their Possible Substrates in Hepatocytes and cDNA-Transfected COS-7 Cells” - August 01, 2002

Abstract

In the present study, we compared the inhibitory effects of organic anions (including bile acids) on the uptake of taurocholate (TC) and estradiol 17β-d-glucuronide (E217βG), typical substrates for sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide (oatp1), respectively, using primary cultured rat hepatocytes and Ntcp- or oatp1-transfected COS-7 cells. The Na+-dependent uptake of TC was inhibited by nine bile acids and five nonbile acid organic anions in a concentration-dependent manner, and their inhibitory effects were similar in both primary cultured rat hepatocytes and Ntcp-transfected COS-7 cells. BQ-123 (1 μM) and indomethacin (10 μM), both of which exhibit no Ntcp-mediated transport, significantly inhibited the Na+-dependent uptake of TC mediated by Ntcp. In addition, the Na+-independent uptake of E217βG was inhibited by 15 organic anions in a concentration-dependent manner, and their inhibitory effects were similar between primary cultured rat hepatocytes and oatp1-transfected COS-7 cells. BQ-123 (1 μM), pravastatin (1 μM), and indomethacin (10 μM), all of which do not undergo oatp1-mediated transport, significantly inhibited the Na+-independent uptake of E217βG mediated by oatp1. These results are consistent with the hypothesis that the hepatic uptake of TC and E217βG is predominantly mediated by Ntcp and oatp1, respectively. In addition, it was clearly demonstrated that we cannot refer to the substrate specificity of transporters based on inhibition studies.

Footnotes

  • Send reprint requests to: Yuichi Sugiyama, Ph.D., Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail:sugiyama{at}seizai.f.u-tokyo.ac.jp.

  • Abbreviations:
    Ntcp
    sodium taurocholate cotransporting polypeptide
    oatp
    organic anion transporting polypeptide
    TC
    taurocholate
    E217βG
    estradiol 17β-d-glucuronide
    BSP
    bromosulfophthalein
    CA
    cholate
    TCDCA
    taurochenodeoxycholate
    CDCA
    chenodeoxycholate
    E3040
    6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole
    DBSP
    dibromosulfophthalein
    GCA
    glycocholate
    LCA
    litocholate
    DCA
    deoxycholate
    UDCA
    ursodeoxycholate
    GCDCA
    glycochenodeoxycholate
    BZP
    benzylpenicillin
    ONO-1301
    7,8-dihydro-5-[(E)-[[a-(3-pyridyl)benzylidene]aminooxy]ethyl]-1-naphthyoxy]acetic acid
    BSP-SG
    glutathione-conjugate of bromosulfophthalein
    DMEM
    Dulbecco's modified Eagle's medium
    • Received July 19, 1999.
    • Accepted September 29, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 2
1 Feb 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of the Transport Properties of Organic Anion Transporting Polypeptide 1 (oatp1) and Na+/Taurocholate Cotransporting Polypeptide (Ntcp): Comparative Studies on the Inhibitory Effect of their Possible Substrates in Hepatocytes and cDNA-Transfected COS-7 Cells

Hirokazu Kouzuki, Hiroshi Suzuki, Bruno Stieger, Peter J. Meier and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1, 2000, 292 (2) 505-511;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Characterization of the Transport Properties of Organic Anion Transporting Polypeptide 1 (oatp1) and Na+/Taurocholate Cotransporting Polypeptide (Ntcp): Comparative Studies on the Inhibitory Effect of their Possible Substrates in Hepatocytes and cDNA-Transfected COS-7 Cells

Hirokazu Kouzuki, Hiroshi Suzuki, Bruno Stieger, Peter J. Meier and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1, 2000, 292 (2) 505-511;
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