Contribution of Xanthine Oxidase-Derived Oxygen Free Radicals to the Development of Carbon Tetrachloride-Induced Acute Liver Injury in Rats

We examined how oxygen free radicals derived from xanthine oxidase (XOD) contribute to the development of carbon tetrachloride (CCl4)-induced acute liver injury in rats. In rats treated with CCl4 (1 ml/kg), liver injury appeared 3 h after the treatment and developed by 24 h, judged from the serum levels of transaminases. Hepatic and serum XOD activities and serum uric acid concentration did not change 6 h after CCl4 treatment, but they all increased at 12 h and further increased at 24 h. An increase in the concentration of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, and decreases in reduced glutathione concentration and Cu,Zn-superoxide dismutase (SOD) activity, but not Mn-SOD activity, were observed in the liver at 6 h after CCl4 treatment and these changes were further enhanced at 24 h. When allopurinol (50 mg/kg), an XOD inhibitor, was administered to CCL4-treated rats 6 h after CCl4 treatment, liver injury progression was prevented with attenuation of increased hepatic and serum XOD activities, serum uric acid concentration, and hepatic TBARS concentration and decreased hepatic reduced glutathione concentration and Cu,Zn-SOD activity at 24 h after CCl4 treatment. These results indicate that XOD-derived oxygen free radicals contribute to the progression of CCl4-induced acute liver injury in rats both by stimulating hepatic lipid peroxidation and by disrupting hepatic antioxidant defense system.