A series of
methylenedioxybenzene compounds were synthesized and found to have hepatoprotective effects in chemical-induced hepatotoxicity models. The purpose of the present study was to investigate the anti-fibrotic effects of a synthetic
methylenedioxybenzene compound,
CW209292, using the
dimethylnitrosamine (DMN)-induced chronic liver injury model in rats. Liver
injuries were induced in Sprague Dawley rats by injection of DMN (intraperitoneally, 10 microl/kg) 3 times per week for 4 weeks. The rats were treated with
CW209292 (per os, 25 or 75 mg/kg/d) for 4 weeks. Treatment of rats with DMN for 4 weeks resulted in significant decreases in
serum albumin levels, whereas concomitant treatment with
CW209292 prevented these decreases.
CW209292 treatment also shortened prothrombin time prolonged by DMN, providing evidence that the agent was active in preserving liver function against DMN insult. DMN treatment caused marked increases in plasma
bilirubin,
aspartate aminotransferase (AST),
alanine transaminase (ALT), and
hyaluronic acid levels;
CW209292 treatment reversed these increases.
CW209292 also significantly reduced hepatic
hydroxyproline content as well as hepatic
fibrosis and
inflammation in histological examination. Additionally, immunochemically detectable hepatic
collagen type IV and alpha-smooth muscle actin levels were decreased by
CW209292 treatment. Proliferation of hepatic stellate cells isolated from DMN-treated rats was inhibited by
CW209292. Furthermore,
tumor growth factor (TGF)-beta1
mRNA expression was increased in DMN-treated rats, whereas
CW209292 treatment prevented these increases. These results suggest that
CW209292 exhibits anti-fibrotic effects in Sprague Dawley rats with DMN-induced hepatic
fibrosis by blocking the
mRNA expression of
TGF-beta1 and subsequent inhibition of the proliferation of hepatic stellate cells.