Protective effects of allopurinol against acute liver damage and cirrhosis induced by carbon tetrachloride: Modulation of NF-κB, cytokine production and oxidative stress

Background: The aim of this work was to evaluate the hepatoprotective ability of allopurinol to prevent the liver injury induced by carbon tetrachloride (CCl4). Methods: Acute liver damage was induced with CCl4 (4 g/kg, by gavage); allopurinol (50 mg/kg, by gavage) was given 1 h before and 1 h after CCl4 intoxication and two daily doses for the previous three days. Cirrhosis was established by CCl4 administration (0.4 g/kg, i.p. three times a week, eight weeks); allopurinol was administered (100 mg/kg, by gavage, daily) during the long-term of CCl4 treatment. Alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gamma-GTP), xanthine oxidase (XO), lipid peroxidation, reduced and oxidized glutathione (GSH. GSSG, respectively), hydroxyproline and histopathologycal analysis were performed. Nuclear factor-kappa B (NF-kappa B), pro-inflammatory and anti-inflammatory cytokines, transforming growth factor-beta (TGF-beta) and metalloproteinase-13 (MMP-13) were analyzed by Western blots. Results: Acute injury increased ALT and gamma-GTP activities, additionally enhanced NF-kappa B nuclear translocation and cytokines production such as tumor necrosis factor-alpha, interleukine-1 beta, and interleukine-6. Allopurinol partially prevented these effects, while increased interleukine-10. Acute and chronic CCl4 treatments altered the levels of XO activity, lipid peroxidation, and GSH/GSSG ratio, while these remained within normal range with allopurinol administration. Necrosis, fibrosis and TGF-beta production induced in chronic injury were partially prevented by allopurinol, interestingly, this drug induced MMP-13 activity. Conclusions: Allopurinol possesses antioxidant, anti-inflammatory and antifibrotic properties, probably by its capacity to reduce NF-kappa B nuclear translocation and TGF-beta expression, as well as to induce MMP-13. General significance: Allopurinol might be effective treatment of liver diseases. (C) 2011 Elsevier B.V. All rights reserved.