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Molecular Pharmacology

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Research ArticleArticle

Impaired Hepatic Uptake by Organic Anion-Transporting Polypeptides Is Associated with Hyperbilirubinemia and Hypercholanemia in Atp11c Mutant Mice

Yusuke Matsuzaka, Hisamitsu Hayashi and Hiroyuki Kusuhara
Molecular Pharmacology December 2015, 88 (6) 1085-1092; DOI: https://doi.org/10.1124/mol.115.100578
Yusuke Matsuzaka
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
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Hisamitsu Hayashi
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
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Hiroyuki Kusuhara
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
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Abstract

Biliary excretion of organic anions, such as bile acids (BAs), is the main osmotic driving force for bile formation, and its impairment induces intrahepatic cholestasis. We investigated the involvement of Atp11c in the hepatic transport of organic anions using Atp11c mutant mice, which exhibit hypercholanemia and hyperbilirubinemia. Pharmacokinetic analysis following a constant intravenous infusion in Atp11c mutant mice showed decreased hepatic sinusoidal uptake and intact biliary secretion of [3H]17β estradiol 17β-d-glucuronide. Consistent with this result, compared with cells and membranes from control mice, isolated hepatocytes, and liver plasma membranes from Atp11c mutant mice had a much lower uptake of [3H]17β estradiol 17β-d-glucuronide and expression of organic anion-transporting polypeptides, which are transporters responsible for hepatic uptake of unconjugated BAs and organic anions, including bilirubin glucuronides. Uptake of [3H]TC into hepatocytes and expression of Na+-taurocholate cotransporting polypeptide in liver plasma membranes, which mediates hepatic uptake of conjugated BAs, was also lower in the Atp11c mutant mice. Bile flow rate, biliary BA concentration, and expression of hepatobiliary transporters did not differ between Atp11c mutant mice and control mice. These results suggest that Atp11c mediates the transport of BAs and organic anions across the sinusoidal membrane, but not the canalicular membrane, by regulating the abundance of transporters. Atp11c is a candidate gene for genetically undiagnosed cases of hypercholanemia and hyperbilirubinemia, but not of intrahepatic cholestasis. This gene may influence the pharmacological and adverse effect of drugs because organic anion-transporting polypeptides regulate their systemic exposure.

Footnotes

    • Received June 27, 2015.
    • Accepted September 22, 2015.
  • ↵1 Y.M. and H.H. contributed equally to this work.

  • This work was supported by a Grant-in-Aid for Scientific Research (C) [Grant 6460192], Astellas Foundation for Research on Metabolic Disorders, and the Department of Research Promotion from Japan Agency for Medical Research and Development, Japan Agency for Research and Development (AMED) [Grant 15ak0101036] to Hisamitsu Hayashi.

  • dx.doi.org/10.1124/mol.115.100578.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (6)
Molecular Pharmacology
Vol. 88, Issue 6
1 Dec 2015
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Research ArticleArticle

Impaired Hepatic Uptake by OATPs in Atp11c Mutant Mice

Yusuke Matsuzaka, Hisamitsu Hayashi and Hiroyuki Kusuhara
Molecular Pharmacology December 1, 2015, 88 (6) 1085-1092; DOI: https://doi.org/10.1124/mol.115.100578

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Research ArticleArticle

Impaired Hepatic Uptake by OATPs in Atp11c Mutant Mice

Yusuke Matsuzaka, Hisamitsu Hayashi and Hiroyuki Kusuhara
Molecular Pharmacology December 1, 2015, 88 (6) 1085-1092; DOI: https://doi.org/10.1124/mol.115.100578
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