title: Elucidation of the hepatoprotective moiety of 5β-scymnol that suppresses paracetamol toxicity in mice.
abstract: The shark bile alcohol, 5β-scymnol, protects mice from the hepatotoxic effects of paracetamol (APAP) overdose. To elucidate the hepatoprotective structural moiety of scymnol, we compared its effect with that of its analogue and natural bile salt, sodium scymnol sulfate, in a clinically relevant model of APAP-induced toxicity. Exposure of healthy male Swiss mice to a toxic overdose of APAP (350 mg/kg, ip) significantly increased serum hepatocellular enzyme activities, decreased hepatocellular glutathione (GSH) levels, and induced severe centrilobular hepatocellular necrosis. Repeated low-dose scymnol (5 mg/kg/day for 7 days, ip) significantly reduced the extent of APAP-induced hepatotoxicity without preventing GSH depletion. Sodium scymnol sulfate, which lacks the tri-hydroxyl-substituted aliphatic side chain of scymnol, failed to reduce the APAP hepatotoxicity or prevent GSH depletion when tested under the same experimental conditions. We conclude that the tri-hydroxyl-substituted aliphatic side chain is the hepatoprotective structural moiety of 5β-scymnol that suppresses APAP-induced cytotoxicity in mice.
authors.affiliation: Natural Products Research Group, School of Health & Biomedical Sciences, RMIT University, PO Box 71, Bundoora, VIC, 3083, Australia.
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Hodges
authors.affiliation: Natural Products Research Group, School of Health & Biomedical Sciences, RMIT University, PO Box 71, Bundoora, VIC, 3083, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Carter
authors.affiliation: Natural Products Research Group, School of Health & Biomedical Sciences, RMIT University, PO Box 71, Bundoora, VIC, 3083, Australia.
authors.forename: Nicolette
authors.initials: N
authors.lastname: Kalafatis
authors.affiliation: Key Centre for Toxicology, School of Health & Biomedical Sciences, RMIT University, PO Box 71, Bundoora, VIC, 3083, Australia.
authors.forename: Paul F A
authors.initials: PF
authors.lastname: Wright
authors.affiliation: Natural Products Research Group, School of Health & Biomedical Sciences, RMIT University, PO Box 71, Bundoora, VIC, 3083, Australia. macrides@rmit.edu.au.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Macrides
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D002777:Cholestanols / Q000494:pharmacology*; D062787:Drug Overdose / Q000378:metabolism / Q000517:prevention & control; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice
chemical_list: D002777:Cholestanols; D000082:Acetaminophen; C074469:scymnol; D005978:Glutathione
keywords: Acetaminophen; Antioxidant; Bile alcohol; Hepatotoxicity; Paracetamol; Scymnol