Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis

Mark Pines, Viktor Knopov, Olga Genina, Irina Lavelin, Arnon Nagler

Research output: Contribution to journalArticlepeer-review

Abstract

Background/Aims: Hepatic cirrhosis is characterized by excessive deposition of collagen, resulting from an increase in type I collagen gene transcription. We evaluated the effect of halofuginone - a specific inhibitor of collagen type α1(I) gene expression - on dimethylnitrosamine (DMN)- induced fiver fibrosis/cirrhosis in rats. Methods: Fibrosis was induced by intraperitoneal injection of DMN. Halofuginone (5 mg/kg) was added to the diet. Collagen was stained with Sirius red and collagen α1(I) gene expression was evaluated by in situ hybridization. Results: In control rats, a low level of collagen α1(I) gene expression was observed. A high dose of DMN (1%) caused severe fibrosis, as indicated by induction of collagen α1(I) gene expression and increased liver collagen content. Addition of halofuginone before the onset of fibrosis, almost completely prevented the increase in collagen type I gene expression and resulted in lower liver collagen content. Moreover, halofuginone partially prevented the marked decrease in liver weight and reduced the mortality rate. At a lower dose of DMN (0.25%), which causes mild fibrosis, halofuginone prevented the increase in collagen α1(I) gene expression, prevented the increase in liver collagen deposition and reduced plasma alkaline phosphatase activity, all of which are characteristic of liver fibrosis/ cirrhosis. Conclusions: These results suggest that halofuginone can be used as an important tool to understand the regulation of the collagen α1(I) gene and may become a novel and promising antifibrotic agent for liver fibrosis/cirrhosis.

Original languageEnglish
Pages (from-to)391-398
Number of pages8
JournalJournal of Hepatology
Volume27
Issue number2
DOIs
StatePublished - Aug 1997
Externally publishedYes

Keywords

  • Collagen
  • Fibrosis
  • Plant alkaloid

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