title: Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant.
abstract: Administration of silymarin (800 mg/kg i.p.) 30 min before carbon tetrachloride (18 microL/kg i.p.) did not modify total hepatic levels of CCl4 and metabolites in mice, but decreased by 40% the in vivo covalent binding of CCl4 metabolites to hepatic lipids at 2 hr. This pretreatment decreased by 60% the exhalation of ethane during the first hour after CCl4, and decreased by 50% the incidence of liver cell necrosis. In vitro, silymarin (800 micrograms/mL) decreased by 50 to 70% various monooxygenase activities, and decreased by 20% the covalent binding of CCl4 metabolites to microsomal proteins. Silymarin (800 micrograms/mL) decreased by 70% in vitro lipid peroxidation mediated by CCl4 metabolites, and decreased by 90% peroxidation mediated by NADPH alone. Silibinin, one of the three isomers composing silymarin, also decreased carbon tetrachloride-induced lipid peroxidation; this effect, however, was less than that of silymarin in vitro, and was more transient in vivo. Pretreatment with silibinin (800 mg/kg i.p.) 30 min before CCl4 (18 microL/kg i.p.) did not improve SGPT activity or liver histology at 24 hr. We conclude that silymarin prevents carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice, firstly, by decreasing the metabolic activation of CCl4, and, secondly, by acting as a chain-breaking antioxidant.
authors.affiliation: Unité de Recherches de Physiopathologie Hépatique (INSERM U-24), Hôpital Beaujon, Clichy, France.
authors.forename: P
authors.initials: P
authors.lastname: Lettéron
authors.forename: G
authors.initials: G
authors.lastname: Labbe
authors.forename: C
authors.initials: C
authors.lastname: Degott
authors.forename: A
authors.initials: A
authors.lastname: Berson
authors.forename: B
authors.initials: B
authors.lastname: Fromenty
authors.forename: M
authors.initials: M
authors.lastname: Delaforge
authors.forename: D
authors.initials: D
authors.lastname: Larrey
authors.forename: D
authors.initials: D
authors.lastname: Pessayre
mesh_terms: D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001667:Binding, Competitive; D002251:Carbon Tetrachloride / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005419:Flavonoids / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D005419:Flavonoids; D012838:Silymarin; D002251:Carbon Tetrachloride; D015660:7-Alkoxycoumarin O-Dealkylase; D000410:Alanine Transaminase