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Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid.

AbstractBACKGROUND/AIMS:
Several studies have indicated increased expression of the Ras protooncogenes in liver cirrhosis. In a previous study in rats, we have shown that a synthetic Ras antagonist, S-farnesylthiosalicylic acid (FTS), could inhibit the development of liver cirrhosis. The aim of the current study was to examine whether FTS will accelerate the resolution of liver cirrhosis induced in rats by thioacetamide.
METHODS:
Cirrhosis was induced in male Wistar rats by intraperitoneal (i.p.) administration of thioacetamide (200 mg/kg twice weekly for 12 weeks). In the treated group, the Ras antagonist FTS (5 mg/kg, i.p./3 times/week) was administered for 8 weeks after liver cirrhosis has already been established. Control cirrhotic rats received PBS injections for 8 weeks.
RESULTS:
Rats treated with FTS for 8 weeks had lower histopathologic score of fibrosis (P = 0.01), lower hepatic hydroxyproline levels (P = 0.0002) and lower spleen weight (P = 0.02) than the cirrhotic rats treated with PBS. Following FTS treatment, the MMP-2 and MMP-9-induced collagenolytic activity and TIMP-2 expression, were increased in FTS-compared to PBS-treated rats. TUNEL assay of liver sections performed 8 weeks after thioacetamide withdrawal showed increased apoptotic figures in both groups (P = NS).
CONCLUSIONS:
These results indicate that the Ras antagonist FTS accelerates the regression of experimentally-induced hepatic cirrhosis. The mechanism may involve increased collagenolytic activity.
AuthorsShimon Reif, Hussein Aeed, Yael Shilo, Reuven Reich, Yoel Kloog, Young Oh Kweon, Rafael Bruck
JournalJournal of hepatology (J Hepatol) Vol. 41 Issue 2 Pg. 235-41 (Aug 2004) ISSN: 0168-8278 [Print] Netherlands
PMID15288472 (Publication Type: Journal Article)
Chemical References
  • Salicylates
  • farnesylthiosalicylic acid
  • Thioacetamide
  • Tissue Inhibitor of Metalloproteinase-2
  • Farnesol
  • Metalloproteases
  • Hydroxyproline
Topics
  • Animals
  • Apoptosis
  • Farnesol (analogs & derivatives, pharmacology)
  • Gene Expression (drug effects)
  • Genes, ras
  • Hydroxyproline (metabolism)
  • In Situ Nick-End Labeling
  • Liver (drug effects, metabolism, pathology, physiopathology)
  • Liver Cirrhosis, Experimental (chemically induced, genetics, pathology, physiopathology)
  • Male
  • Metalloproteases (metabolism)
  • Organ Size (drug effects)
  • Rats
  • Rats, Wistar
  • Salicylates (pharmacology)
  • Spleen (pathology)
  • Thioacetamide
  • Tissue Inhibitor of Metalloproteinase-2 (metabolism)

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