Potent antioxidant role of pirfenidone in experimental cirrhosis

Eur J Pharmacol. 2008 Oct 24;595(1-3):69-77. doi: 10.1016/j.ejphar.2008.06.110. Epub 2008 Jul 9.


Three important features must be considered when proposing therapeutic strategies in liver cirrhosis: inflammation, oxidative stress and fibrogenesis. Pirfenidone is a synthetic molecule which oxidative action has not been tested in cirrhosis. Cirrhosis was induced in rats by ligation of the common bile duct or carbon tetrachloride (CCl(4)) chronic intoxication and treated with pirfenidone or diphenyleneiodonium (a potent known antioxidant) for the last two weeks for bile duct ligation model or for the last three weeks for CCl(4) chronic intoxication. A 60% reduction in fibrosis index for bile duct ligation model and 42% for CCl(4) along with reduced inflammation was observed. Considerable reduction on hepatic enzymes and total and direct bilirubins were detected with pirfenidone in both models. Pirfenidone antioxidant capacity rendered a 28% and 30% reduction in nitrites and malonyldealdehide concentration in bile duct ligation and 52% and 38% in CCl(4). With respect to gene expression, fibrotic genes like transforming growth factor-beta (TGF-beta) and collagen Ialpha (Col-1alpha) were down-regulated by pirfenidone and increased expression of regenerative genes like hepatocyte growth factor (HGF) and c-met . Superoxide dismutase (SOD), catalase (CAT) and inducible nitric oxide synthase (iNOS) gene expression were importantly down-regulated where nuclear factor kappa B (NF-kappaB) binding activity also decreased with pirfenidone treatment. Also, SOD and CAT functional activity decreased after pirfenidone action. On the other hand, diphenyleneiodonium induced a drop in oxidative stress similar in extent to pirfenidone, but it was not as effective as pirfenidone in reducing fibrosis. In this work, we showed antioxidant properties of pirfenidone beyond its well-known antifibrotic effect. These features make pirfenidone an attractive drug for trying fibrotic diseases accompanied by oxidative stress processes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Antioxidants / pharmacology*
  • Aspartate Aminotransferases / blood
  • Bilirubin / blood
  • Carbon Tetrachloride
  • Catalase / genetics
  • Catalase / metabolism
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Common Bile Duct / surgery
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Ligation
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Liver Cirrhosis, Experimental / enzymology
  • Liver Cirrhosis, Experimental / etiology
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / prevention & control*
  • Malondialdehyde / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Nitrites / metabolism
  • Onium Compounds / pharmacology*
  • Oxidative Stress / drug effects*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridones / pharmacology*
  • Rats
  • Rats, Wistar
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism


  • Antioxidants
  • Collagen Type I
  • NF-kappa B
  • Nitrites
  • Onium Compounds
  • Pyridones
  • Transforming Growth Factor beta
  • Malondialdehyde
  • Hepatocyte Growth Factor
  • diphenyleneiodonium
  • Carbon Tetrachloride
  • pirfenidone
  • Catalase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Superoxide Dismutase
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Proto-Oncogene Proteins c-met
  • Bilirubin