title: Hepatotoxic effect of (+)usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria.
abstract: Hepatotoxic effect of (+)usnic acid, the active constituent of Usnea siamensis Wainio was studied in rats, isolated rat hepatocytes and isolated rat liver mitochondria. In rats, after treatment with high dose of (+)usnic acid (200 mg/kg per day, i.p.) for 5 days, there was no significant change in serum transaminase activity (serum AST, ALT) while the electron micrographs showed apparent morphological damage of mitochondria and endoplasmic reticulum. (+)Usnic acid at high dose (1 mM) as well as carbon tetrachloride (CCl4, the reference hepatotoxin) induced loss of cell membrane integrity in isolated rat hepatocytes by increasing the release of cellular transaminases (AST, ALT). Increase in lipid peroxidation, decrease in glutathione (GSH) content and increase in aniline hydroxylase activity (CYP 2E1) were also found. Combination of (+)usnic acid and CCl4 showed the additive results. (+)Usnic acid (0.15-6 microM) possessed uncoupling activity in isolated rat liver mitochondria. It stimulated respiration by mitochondria respiring with glutamate plus malate or succinate as substrates and activated ATPase activity. Increasing concentration of (+)usnic acid (>6 microM) exhibited loss of respiratory control and ATP synthesis. In conclusion, hepatotoxic effect of high dose (+)usnic acid may involve its reactive metabolite(s), causing loss of integrity of membrane like structures, resulting in destruction of mitochondrial respiration and oxidative phosphorylation.
authors.affiliation: Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Pornpen
authors.initials: P
authors.lastname: Pramyothin
authors.forename: Withaya
authors.initials: W
authors.lastname: Janthasoot
authors.forename: Nushjira
authors.initials: N
authors.lastname: Pongnimitprasert
authors.forename: Siriwan
authors.initials: S
authors.lastname: Phrukudom
authors.forename: Nijsiri
authors.initials: N
authors.lastname: Ruangrungsi
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020949:Usnea
chemical_list: D001572:Benzofurans; C073339:usnic acid