S-adenosylmethionine protects against acetaminophen hepatotoxicity in two mouse models.
Because S-adenosylmethionine promotes synthesis of hepatic glutathione in chronic liver disease and is well tolerated in man, we investigated its use as an antidote to acetaminophen hepatotoxicity in two mouse models. In C57Bl6 mice, deaths were abolished by S-adenosylmethionine given within 1 hr of 3.3 mmol/kg body wt acetaminophen (0 of 32 vs. 13 of 49, p less than 0.005) and reduced if given 2 to 5 hours after acetaminophen administration (4 of 42 vs. 13 of 49, p less than 0.01). Mixed disulfate/tosylate salt of S-adenosylmethionine abolished mortality in C3H mice given 2 mmol/kg body wt acetaminophen (0 of 24 vs. 4 of 18; p less than 0.05). In both mouse models, S-adenosylmethionine reduced depletion of plasma (median = 20.8 mumol/L vs. 14.6 mumol/L) and liver glutathione (198% vs. 100%; p less than 0.05), liver damage and release of AST after acetaminophen administration. Pretreatment with buthionine sulfoximine, which inhibits glutathione synthesis, abolished the beneficial effect of S-adenosylmethionine on survival and plasma glutathione level. S-adenosylmethionine reduces acetaminophen hepatotoxicity by metabolism of the active moiety to glutathione. This benefit may last as long as 5 hr after acetaminophen ingestion.
Bray
G P
GP
Institute of Liver Studies, King's College Hospital School of Medicine and Dentistry, Denmark Hill, London, United Kingdom.
Tredger
J M
JM
Williams
R
R
D000082:Acetaminophen / Q000009:adverse effects*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009026:Mortality; D012436:S-Adenosylmethionine / Q000494:pharmacology*
D008717:Methionine Sulfoximine; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D012436:S-Adenosylmethionine; D008715:Methionine; D000111:Acetylcysteine