Bray G P, Tredger J M, Williams R
Institute of Liver Studies, King's College Hospital School of Medicine and Dentistry, Denmark Hill, London, United Kingdom.
Hepatology. 1992 Feb;15(2):297-301. doi: 10.1002/hep.1840150220.
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.
由于S-腺苷甲硫氨酸可促进慢性肝病中肝脏谷胱甘肽的合成，且在人体中耐受性良好，我们在两种小鼠模型中研究了其作为对乙酰氨基酚肝毒性解毒剂的用途。在C57Bl6小鼠中，在给予3.3 mmol/kg体重对乙酰氨基酚后1小时内给予S-腺苷甲硫氨酸可消除死亡（32只中0只死亡 vs. 49只中13只死亡，p<0.005），如果在给予对乙酰氨基酚后2至5小时给予则死亡减少（42只中4只死亡 vs. 49只中13只死亡，p<0.01）。S-腺苷甲硫氨酸的混合硫酸氢盐/甲苯磺酸盐可消除给予2 mmol/kg体重对乙酰氨基酚的C3H小鼠的死亡率（24只中0只死亡 vs. 18只中4只死亡；p<0.05）。在两种小鼠模型中，S-腺苷甲硫氨酸均可减少对乙酰氨基酚给药后血浆谷胱甘肽（中位数=20.8 μmol/L vs. 14.6 μmol/L）和肝脏谷胱甘肽（198% vs. 100%；p<0.05）的消耗、肝脏损伤及AST的释放。用抑制谷胱甘肽合成的丁硫氨酸亚砜胺预处理可消除S-腺苷甲硫氨酸对生存和血浆谷胱甘肽水平的有益作用。S-腺苷甲硫氨酸通过将活性部分代谢为谷胱甘肽来降低对乙酰氨基酚的肝毒性。这种益处可能在摄入对乙酰氨基酚后持续长达5小时。
