Gerson R J, Casini A, Gilfor D, Serroni A, Farber J L
Biochem Biophys Res Commun. 1985 Feb 15;126(3):1129-37. doi: 10.1016/0006-291x(85)90303-1.
Sensitivity of cultured hepatocytes to acetaminophen was induced by pretreatment of the rat with 3-methylcholanthrene. Under these conditions, 10 uM B-naphthoflavone but not SKF-525A prevented the cell killing, indicating dependence on metabolism. Inhibition of glutathione reductase by 50 uM bis-chloro-nitrosourea, shown previously to increase the sensitivity of hepatocytes to an oxidative stress, potentiated the toxicity of acetaminophen without increasing the covalent binding of acetaminophen metabolites. Pretreatment of the hepatocytes with the ferric iron chelator deferoxamine, known to reduce the sensitivity of hepatocytes to an oxidative stress, prevented the cell killing without reducing covalent binding. Addition of ferric chloride to the culture medium restored the sensitivity of the cells to acetaminophen, again without effect on the extent of covalent binding. These data demonstrate that the toxicity of acetaminophen can be dissociated from the covalent binding of its metabolites and support the conclusion that the hepatocytes were lethally injured by an oxidative stress accompanying the mixed function oxidase-dependent biotransformation of acetaminophen.
用3 - 甲基胆蒽对大鼠进行预处理可诱导培养的肝细胞对乙酰氨基酚的敏感性。在这些条件下，10 μM的β - 萘黄酮可防止细胞死亡，但SKF - 525A却不能，这表明细胞死亡依赖于代谢。50 μM双氯亚硝基脲对谷胱甘肽还原酶的抑制作用（先前已表明该抑制作用会增加肝细胞对氧化应激的敏感性）增强了乙酰氨基酚的毒性，但并未增加乙酰氨基酚代谢产物的共价结合。用铁螯合剂去铁胺对肝细胞进行预处理（已知去铁胺可降低肝细胞对氧化应激的敏感性）可防止细胞死亡，且不降低共价结合。向培养基中添加氯化铁可恢复细胞对乙酰氨基酚的敏感性，同样对共价结合程度无影响。这些数据表明，乙酰氨基酚的毒性可与其代谢产物的共价结合相分离，并支持以下结论：肝细胞因伴随乙酰氨基酚混合功能氧化酶依赖性生物转化的氧化应激而受到致命损伤。
