title: 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.affiliation: Department of Pharmacology, National Research Centre, Tahrir St., Dokki, Cairo, Egypt. omasalam@hotmail.com
authors.forename: Omar Mohamed E
authors.initials: OM
authors.lastname: Abdel Salam
authors.forename: Amany A
authors.initials: AA
authors.lastname: Sleem
authors.forename: Nermeen
authors.initials: N
authors.lastname: Shafee
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001769:Blood / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D005260:Female; D005978:Glutathione / Q000097:blood; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012838:Silymarin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D020030:Nitric Oxide Donors; D012838:Silymarin; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D005978:Glutathione; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate