Allopurinol protects against acute liver damage and prevents and reverses cirrhosis
Allopurinol protects against acute liver damage and prevents and reverses cirrhosis induced by carbon tetrachloride: role of cytokines modulation and oxidative stress.
Allopurinol is an inhibitor of xanthine oxidase (XO). XO generates reactive oxygen species which have been proposed to act as inflammation mediators. The aim of this work was to evaluate the efficacy and the hepatoprotective mechanism of allopurinol to prevent and to reverse the liver injury induced by carbon tetrachloride (CCl4). Male Wistar rats were used with n=8 for each group. Acute liver injury was induced by a CCl4 (4 g/kg, i. p.); in another group, allopurinol (50 mg/kg, p. o.) was given 1 h before and 1 h after CCl4 administration and two daily doses for the previous three days. Rats were sacrificed 24 h after CCl4 administration. Cirrhosis was induced by chronic CCl4 administration (0.4 g/kg, i. p. three times a week for eight weeks). To test if allopurinol prevents cirrhosis, a group received a daily dose of allopurinol (100 mg/kg, p. o.) during the chronic CCl4 treatment, and to test if allopurinol reverses cirrhosis, this drug was administered (100 mg/kg, p. o., daily) during four weeks after chronic CCl4 administration. Rats were sacrificed at the end of treatments including control groups. Histopathologycal analysis, alanine amino transferase (ALT), hydroxyproline, glycogen, reduced and oxidized glutathione (GSH/GSSG), lipid peroxidation and XO levels were assessed. Also cytokines were analyzed by Western blots. Acute injury increased ALT activity and the pro-inflammatory cytokines production mainly the tumor necrosis factor-α (TNF-α) and interleukine-1β (IL-1β), allopurinol prevented partially these effects while increased anti-inflammatory interleukine-10 (IL-10). Acute and chronic CCl4 treatments altered the levels of lipid peroxidation, XO activity and GSH/GSSG ratio, while these levels remained within normal range with allopurinol treatment. Necrosis, fibrosis and transforming growth factor-β (TGF-β) production induced in chronic injury were partially prevented by allopurinol. In the chronic injury induced by CCl4 the ALT, glycogen and oxidative stress values were in normal range by allopurinol treatment, while TGF-β production and fibrosis were significantly reverted. ALT and hydroxyproline results were consistent with histopathologycal stains. These findings suggest that allopurinol prevents acute and chronic liver injuries by several mechanisms: reducing oxidative stress; modulating the expression of pro-inflammatory and anti-inflammatory cytokines; and possesses anti-fibrotic and fibrolytic properties probably by its ability to modulate TGF-β expression.
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