Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis.
OBJECTIVE
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 alpha 1(I) gene expression-on dimethylnitrosamine (DMN)-induced liver 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 alpha 1(I) gene expression was evaluated by in situ hybridization.


RESULTS
In control rats, a low level of collagen alpha 1(I) gene expression was observed. A high dose of DMN (1%) caused severe fibrosis, as indicated by induction of collagen alpha 1(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 alpha 1(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 alpha 1(I) gene and may become a novel and promising antifibrotic agent for liver fibrosis/ cirrhosis.
Pines
M
M
Institute of Animal Science, Volcani Center, Bet Dagan, Israel. vlmpines@volcani.agri.gov.il
Knopov
V
V
Genina
O
O
Lavelin
I
I
Nagler
A
A
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000235:genetics; D004128:Dimethylnitrosamine; D015870:Gene Expression / Q000187:drug effects; D017403:In Situ Hybridization; D007274:Injections, Intraperitoneal; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010880:Piperidines; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D051381:Rats; D017207:Rats, Sprague-Dawley
D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D003094:Collagen; D000469:Alkaline Phosphatase; C010176:halofuginone; D004128:Dimethylnitrosamine