: We reported that melatonin prevents the progression of carbon tetrachloride (CCl4)‐induced acute liver injury in rats possibly by attenuating enhanced lipid peroxidation and reduced glutathione depletion. Herein, we examined the effect of melatonin on the changes in hepatic reactive oxygen species (ROS) metabolism in rats with a single intraperitoneal injection of CCl4 (1.6 g/kg body weight); the intent was to clarify the therapeutic mechanism of the indoleamine on CCl4‐induced acute liver injury. Rats with and without CCl4 treatment received a single oral dose of melatonin (10, 50 or 100 mg/kg body weight) 6 hr after CCl4 treatment. Hepatic concentrations of ascorbic acid (ASC) and vitamin E (VE) and hepatic activities of superoxide dismutase (SOD), catalase (CAT), Se‐glutathione peroxidase (Se‐GSH‐Px), glutathione reductase (GSSG‐R), glucose‐6‐phosphate dehydrogenase (G‐6‐PDH), and xanthine oxidase (XO) were determined 6 and 24 hr after CCl4 treatment. The liver of CCl4‐treated rats showed reductions in ASC concentrations, and SOD activity and an increase in G‐6‐PDH activity at 6 hr after treatment and further decreases in ACS concentrations and SOD activity and also further increase in G‐6‐PDH activity in addition to decreases in CAT and GSSG‐R activities and increases in VE concentrations and XO activity at 24 hr after treatment. Melatonin attenuated the reductions in hepatic ASC concentrations and SOD, CAT and GSSG‐R activities and the increase in hepatic XO activity in a dose‐dependent manner without affecting either hepatic Se‐GSH‐Px activity or the increased hepatic VE concentration and G‐6‐PDH activity at 24 hr after CCl4 treatment. No dose of melatonin influenced hepatic ACS and VE concentrations and SOD, CAT, Se‐GSH‐Px, G‐6‐PDH, and XO activities in CCl4‐untreated rats. These results indicate that melatonin postadministered at pharmacological doses prevents the disruption of hepatic ROS metabolism associated with ASC, SOD, CAT, GSSG‐R, and XO, in addition to reduced glutathione, in CCl4‐treated rats.
Summary 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 b h after CCl4 treatment and these changes were further enhanced at 24h. 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.
The present study was performed to examine whether melatonin attenuates disruption of serum cholesterol status in rats treated once with alpha-naphthylisothiocyanate (ANIT). In the serum of rats treated with ANIT (75 mg/kg, i.p.), increases in total cholesterol, free cholesterol (F-Chol), low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and total bile acid concentrations and a decrease in the ratio of esterified cholesterol concentration to F-Chol concentration occurred 24 hr, but not 12 hr, after the treatment. In the liver of ANIT-treated rats, a decrease in cholesterol concentration and an increase in total bile acid concentration occurred 24 hr, after 12 hr, after the treatment. When melatonin (10 or 100 mg/kg, p.o.) was administered to ANIT-treated rats at 12 hr after the treatment, all these changes found in the serum and liver at 24 hr after the treatment were significantly attenuated at the higher dose. Melatonin (100 mg/kg) administered to ANIT-untreated rats in the same manner increased the serum F-Chol and high-density lipoprotein cholesterol concentrations significantly. These results indicate that orally administered melatonin attenuates the disruption of serum cholesterol status in rats treated once with ANIT possibly by maintaining cholesterol metabolism and transport in the serum and liver.
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