Decreased collagen accumulation by a prolyl hydroxylase inhibitor in pig serum-induced fibrotic rat liver

Authors

  • Kenji Fujiwara M.D.,

    Corresponding author
    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
    • First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7–3–1 Hongo, Bunkyo-ku, Tokyo 113, Japan
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  • Itsuro Ogata,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Yasuhiko Ohta,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Shigeki Hayashi,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Shunji Mishiro,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Katsuyoshi Takatsuki,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Yuzuru Sato,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Shinwa Yamada,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Keichi Hirata,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Hiroshi Oka,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Toshitsugu Oda,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Hisanori Kawaji,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Shinobu Matsuda,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Yasuhiko Niiyama,

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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  • Ryoichi Tsukuda

    1. First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, National Medical Center, Tokyo, and Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
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Abstract

Hepatic fibrosis was induced in rats by repeated i.p. injections of pig serum. The hepatic hydroxyproline content increased to 2.1 times the normal control level at 6 weeks and to 3.2 times at 10 weeks. When P-1894B, an inhibitor of prolyl hydroxylase, was administered, there was a dose-dependent inhibition of the increase to nearly normal control levels at 6 and 10 weeks. There was also by histology a dose-dependent reduction in the degree of hepatic fibrosis. Hepatocellular damage was minimal and its extent did not vary with the degree of fibrosis or the treatment. P-1894B dose dependently reduced the hydroxylation of peptidyl proline in the fibrotic liver. These data suggest that P-1894B inhibited hepatic fibrogenesis by direct action on collagen but not by protection against hepatocellular damage leading to collagen formation. A prolyl hydroxylase inhibitor may be a candidate for use in treatment of hepatic fibrosis.

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