Anti-fibrotic Effects of a Methylenedioxybenzene Compound, CW209292 on Dimethylnitrosamine-Induced Hepatic Fibrosis in Rats

• Published in: Biological & Pharmaceutical Bulletin Vol. 32; no. 8; pp. 1364 - 1370
• Main Authors: Oh, Se-Woong, Kim, Dae-Hoon, Ha, Jong-Ryul, Kim, Dae-Yong
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-08-2009; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Animals; Benzodioxoles - chemistry; Benzodioxoles - pharmacology; Benzodioxoles - therapeutic use; Body Weight - drug effects; Cell Proliferation - drug effects; CW209292; dimethylnitrosamine; Dimethylnitrosamine - toxicity; Disease Models, Animal; Female; hepatic fibrosis; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - pathology; Hydroxyproline - metabolism; Immunohistochemistry; Liver - drug effects; Liver - enzymology; Liver - metabolism; Liver - pathology; Liver Cirrhosis - blood; Liver Cirrhosis - chemically induced; Liver Cirrhosis - pathology; Liver Cirrhosis - prevention & control; Male; methylenedioxybenzene; Molecular Structure; Prothrombin Time; rat; Rats; Rats, Sprague-Dawley; Survival Analysis; Thiazoles - chemistry; Thiazoles - pharmacology; Thiazoles - therapeutic use
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.32.1364

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 μl/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 α-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)-β1 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-β1 and subsequent inhibition of the proliferation of hepatic stellate cells.