Preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation in rats

  1. Kazunori Maeda1,
  2. Masahiko Koda1,*,
  3. Tomomitsu Matono1,
  4. Takaaki Sugihara1,
  5. Satoru Yamamoto1,
  6. Masaru Ueki1,
  7. Yoshikazu Murawaki1,
  8. Nobuyuki Yamashita2,
  9. Shoji Nishiyama2,3

Article first published online: 5 MAR 2008

DOI: 10.1111/j.1872-034X.2008.00326.x

Issue

Hepatology Research

Hepatology Research

Volume 38, Issue 7, pages 727–735, July 2008

Additional Information

How to Cite

Maeda, K., Koda, M., Matono, T., Sugihara, T., Yamamoto, S., Ueki, M., Murawaki, Y., Yamashita, N. and Nishiyama, S. (2008), Preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation in rats. Hepatology Research, 38: 727–735. doi: 10.1111/j.1872-034X.2008.00326.x

Author Information

  1. 1

    Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago,

  2. 2

    Pharmaceutical Research Center, Meiji Seika, Yokohama, and

  3. 3

    Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

*Professor Masahiko Koda, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago 683-8504, Japan. Email: masakoda@grape.med.tottori-u.ac.jp

Publication History

  1. Issue published online: 5 MAR 2008
  2. Article first published online: 5 MAR 2008
  3. Received 13 July 2007; revision 5 December 2007; accepted 18 December 2007.

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Keywords:

  • bile duct ligation;
  • hepatic stellate cells;
  • ME3738;
  • oxidative stress

Aim:  The aim of this study was to examine the preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation (BDL) in rats.

Methods:  ME3738 (20 mg/day) was administered orally for 21 days immediately after BDL. Fibrosis was assessed by measuring hepatic hydroxyproline (Hyp) content. Activated hepatic stellate cells (HSCs) were assessed by α-smooth muscle actin (α-SMA) immunostaining. Hepatic thiobarbituric acid-reactive substance (TBARS), 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2-deoxyguanosine (8-OHdG) immunostaining were used to analyze oxidative stress. The gene expressions of collagen-I, transforming growth factor-β1 (TGF-β1), tissue inhibitor of metalloproteinases-1 (TIMP-1), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) in the liver were examined by real-time reverse transcriptase polymerase chain reaction (RT–PCR).

Results:  Hepatic Hyp content and the area of hepatic fibrosis in BDL rats treated with ME3738 were reduced by 24% and 39% compared with non-treated BDL rats (hepatic Hyp, 9.40 ± 2.85 vs. 12.39 ± 3.91 mg/liver; P = 0.036; area of hepatic fibrosis, 13.1 ± 3.8 vs. 21.5 ± 10.9; P = 0.045). Furthermore, α-SMA-positive cells were significantly reduced by 40% (22.3 ± 14.8 vs. 37.6 ± 14.2; P = 0.011), collagen-I mRNA by 83% (6.5 ± 2.2 vs. 38.3 ± 9.1; P = 0.002), HO-1 mRNA by 58% (4.13 ± 1.22 vs. 9.73 ± 1.80; P = 0.018) and hepatic HO-1 content by 26% (2.13 ± 0.80 vs. 2.87 ± 0.19; P = 0.01) following ME3738 treatment. The hepatic expression of TBARS, 4-HNE, 8-OHdG and mRNA levels of TGF-β1, TIMP-1 and IL-6 in the liver were unchanged by ME3738 treatment.

Conclusion:  Oral ME3738 administration may prevent the progression of hepatic fibrosis in BDL rats through suppression of the activation and collagen synthesis of HSC and, in part, oxidative stress. ME3738 has potential as a therapeutic drug for cholestatic liver fibrosis.

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