Melatonin attenuates disruption of serum cholesterol status in rats with a single alpha-naphthylisothiocyanate treatment.

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.

Saikokeishito Extract Exerts a Therapeutic Effect on alpha-Naphthylisothiocyanate-Induced Liver Injury in Rats through Attenuation of Enhanced Neutrophil Infiltration and Oxidative Stress in the Liver Tissue.

We examined whether Saikokeishito extract (TJ-10), a traditional Japanese herbal medicine, exerts a therapeutic effect on alpha-naphthylisothiocyanate (ANIT)-induced liver injury in rats through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue. In rats treated once with ANIT (75 mg/kg, i.p.), liver injury with cholestasis occurred 24 h after treatment and progressed at 48 h. When ANIT-treated rats orally received TJ-10 (0.26, 1.3 or 2.6 g/kg) at 24 h after the treatment, progressive liver injury with cholestasis was significantly attenuated at 48 h after the treatment at the dose of 1.3 or 2.6 g/kg. At 24 h after ANIT treatment, increases in hepatic lipid peroxide and reduced glutathione contents and myeloperoxidase activity occurred with decreases in hepatic superoxide dismutase and glutathione reductase activities. At 48 h after ANIT treatment, these changes except for reduced glutathione were enhanced with decreases in catalase, Se-glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities. TJ-10 (1.3 or 2.6 g/kg) post-administered to ANIT-treated rats attenuated these changes found at 48 h after the treatment significantly. These results indicate that TJ-10 exerts a therapeutic effect on ANIT-induced liver injury in rats possibly through attenuation of enhanced neutrophil infiltration and oxidative stress in the liver tissue.

alpha-Tocopherol protects against alpha-naphthylisothiocyanate-induced hepatotoxicity in rats less effectively than melatonin.

The protective effect of alpha-tocopherol (alpha-Toc), which exerts antioxidant and anti-inflammatory actions, against alpha-naphthylisothiocyanate (ANIT)-induced hepatotoxicity in rats was compared with that of melatonin because orally administered melatonin is known to protect against ANIT-induced hepatotoxicity in rats through its antioxidant and anti-inflammatory actions. Rats intoxicated once with ANIT (75 mg/kg, intraperitoneal (i.p.)) showed liver cell damage and biliary cell damage with cholestasis at 24 h, but not 12 h, after intoxication. ANIT-intoxicated rats received alpha-Toc (100 or 250 mg/kg) or melatonin (100 mg/kg) orally at 12 h after intoxication. The alpha-Toc administration protected against liver cell damage in ANIT-intoxicated rats, while the melatonin administration protected against both liver cell damage and biliary cell damage with cholestasis. ANIT-intoxicated rats had increased hepatic lipid peroxide concentration and myeloperoxidase activity at 12 and 24 h after intoxication. ANIT-intoxicated rats also had increased serum alpha-Toc and non-esterified fatty acid (NEFA) concentrations at 12 and 24 h after intoxication and increased serum triglyceride and total cholesterol concentrations at 24h. The administration of alpha-Toc to ANIT-intoxicated rats increased the hepatic alpha-Toc concentration with further increase in the serum alpha-Toc concentration and attenuated the increased hepatic lipid peroxide concentration and myeloperoxidase activity and serum NEFA concentration at 24 h after intoxication. The melatonin administration did not affect the hepatic alpha-Toc concentration but attenuated the increased hepatic lipid peroxide concentration and myeloperoxidase activity and serum alpha-Toc, NEFA, triglyceride, and total cholesterol concentrations at 24 h after ANIT intoxication. These results indicate that orally administered alpha-Toc protects against ANIT-induced hepatotoxicity in rats possibly through its antioxidant and anti-inflammatory actions less effectively than orally administered melatonin.

Effect of Oren-gedoku-to (Huanglian-Jie-Du-Tang) extract on disruption of hepatic antioxidant defense systems in rats treated with D-galactosamine.

We have indicated that the antioxidant action of Oren-gedoku-to (Huanglian-Jie-Du-Tang) extract (TJ-15), a traditional Chinese herbal medicine, may contribute to its preventive effect on the progression of D-galactosamine (GAL)-induced liver injury in rats. Herein, we examined a possibility that TJ-15 exerts this preventive effect by attenuating the disruption of hepatic antioxidant defense systems in GAL-treated rats. TJ-15 (500 mg/kg) was orally administered to rats injected with GAL (500 mg/kg, i.p.) at 6 h after hepatotoxin treatment. In the liver of rats treated with GAL alone, the concentration of thiobarbituric acid-reactive substances (TBARS), an index of lipid peroxidation, increased at 24 h, but not at 6 h, while reduced glutathione (GSH) and ascorbic acid concentrations and superoxide dismutase (SOD), catalase, and Se-glutathione peroxidase (Se-GSH-px) activities decreased at 24 h, but not at 6 h. Post-administered TJ-15 prevented all these changes observed at 24 h after GAL treatment. TJ-15 administered to GAL-untreated rats in the same manner did not affect the hepatic TBARS, GSH, and ascorbic acid concentrations and SOD, catalase, and Se-GSH-px activities. These results indicate that post-administered TJ-15 attenuates the disruption of hepatic antioxidant defense systems in GAL-treated rats, which may contribute to its preventive effect on the progression of GAL-induced liver injury.

Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride.

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.