Hepatoprotective effects of the nitric oxide donor isosorbide-5-mononitrate alone and in combination with the natural hepatoprotectant, silymarin, on carbon tetrachloride-induced hepatic injury in rats.

Abstract

The aim of this study was to investigate the effect of the nitric oxide donor isosorbide-5-mononitrate (5-ISMN) alone or in combination with the natural hepatoprotectant with anti-oxidant activity silymarin on the carbon tetrachloride (CCl(4))-induced hepatic injury in rats. 5-ISMN (1.8, 3.6 or 7.2 mg/kg), silymarin (25 mg/kg) or 5-ISMN (1.8, 3.6 or 7.2 mg/kg) combined with silymarin was given once daily orally simultaneously with CCl(4) and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. 5-ISMN given at the above doses conferred significant protection against the hepatotoxic actions of CCl(4) in rats, reducing serum alanine aminotransferase (ALT) levels by 31.2, 39.3 and 61.6%, respectively, when compared with controls. Serum aspartate aminotransferase (AST) levels decreased by 19.8, 22.7 and 59.4%, respectively, while alkaline phosphatase (ALP) decreased by 26.1 and 32.6% by the drug at 3.6 and 7.2 mg/kg, respectively. When silymarin was added to 5-ISMN (1.8, 3.6 or 7.2 mg/kg), ALT decreased by 32.8, 59.6, 70.2% and AST by 28.7, 50.3, 60%, when compared with CCl(4) control group levels. Silymarin in combination with 3.6 or 7.2 mg/kg 5-ISMN resulted in 37.5 and 39.2% reductions in ALP when compared with CCl(4) control group. Meanwhile, silymarin alone reduced ALT, AST and ALP levels by 65.9, 52 and 62.3%, respectively. Blood levels of reduced glutathione were markedly decreased in CCl(4)-treated rats. Reduced glutathione levels were increased by the administration of 5-ISMN and restored to near normal values by silymarin treatment. Histopathological alterations by CCl(4) were markedly reduced after treatment with 5-ISMN alone or in combination with silymarin. Histopathologic examination of the livers of CCl(4)-treated rats administered 5-ISMN at 7.2 mg/kg showed marked restoration of the normal architecture of the liver tissue and minimal fibrosis. Silymarin co-administered with 5-ISMN resulted in further improvement of the histologic picture. These results indicates that treatment with 5-ISMN protects against hepatocellular necrosis induced by CCl(4). The study suggests a potential therapeutic use for 5-ISMN in combination with silymarin in liver injury.

• Authors: Omar Mohamed E Abdel Salam, Amany A Sleem, Nermeen Shafee
• Journal: Inflammopharmacology (Inflammopharmacology) Vol. 18 Issue 2 Pg. 87-94 (Apr 2010) ISSN: 1568-5608 [Electronic] Switzerland
• PMID: 20069380 (Publication Type: Journal Article)

Chemical References

• Nitric Oxide Donors
• Silymarin
• Carbon Tetrachloride
• Aspartate Aminotransferases
• Alanine Transaminase
• Alkaline Phosphatase
• Glutathione
• Isosorbide Dinitrate
• isosorbide-5-mononitrate

Topics

• Alanine Transaminase (blood)
• Alkaline Phosphatase (blood)
• Animals
• Aspartate Aminotransferases (blood)
• Blood (drug effects)
• Carbon Tetrachloride (administration & dosage, pharmacology)
• Chemical and Drug Induced Liver Injury (blood, pathology, prevention & control)
• Drug Therapy, Combination
• Female
• Glutathione (blood)
• Isosorbide Dinitrate (analogs & derivatives, pharmacology, therapeutic use)
• Liver (drug effects, pathology)
• Male
• Nitric Oxide Donors (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Silymarin (pharmacology, therapeutic use)