Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: protection by melatonin and cranberry flavonoids

Toxicol Appl Pharmacol. 2012 Jun 15;261(3):271-9. doi: 10.1016/j.taap.2012.04.007. Epub 2012 Apr 14.


In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride - induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p<0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl₄ displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl₄, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Alanine Transaminase / blood
  • Animals
  • Antioxidants / pharmacology*
  • Aspartate Aminotransferases / blood
  • Bilirubin / blood
  • Carbon Tetrachloride Poisoning / pathology*
  • Chronic Disease
  • Flavonoids / pharmacology*
  • Indicators and Reagents
  • Male
  • Melatonin / pharmacology*
  • Microscopy, Electron
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / pathology*
  • Mitochondria, Liver / ultrastructure
  • Nitric Oxide / blood
  • Oxidative Stress / drug effects
  • Oxygen Consumption / drug effects
  • Rats
  • Rats, Wistar
  • Succinate Dehydrogenase / metabolism
  • Succinates / pharmacology
  • Urea / blood
  • Vaccinium macrocarpon / chemistry*


  • Antioxidants
  • Flavonoids
  • Indicators and Reagents
  • Succinates
  • Nitric Oxide
  • Urea
  • Succinate Dehydrogenase
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Melatonin
  • Bilirubin