Oxygen-mediated cell injury in the killing of cultured hepatocytes by acetaminophen.
Oxygen-mediated cell injury in the killing of cultured hepatocytes by acetaminophen.
复制标题
对乙酰氨基酚杀死培养的肝细胞时氧介导的细胞损伤。
DOI：
10.1016/0006-291x(85)90303-1
复制
发表时间：
1985
影响因子：
3.1
通讯作者：
Farber,JL
中科院分区：
文献类型：
--
作者：
Gerson,RJ;Casini,A;Gilfor,D;Serroni,A;Farber,JL
用3-甲基胆蒽预处理大鼠，诱导培养的肝细胞对对乙酰氨基酚的敏感性。在这些条件下，10 μ M β-萘酚酮而非SKF-525 A阻止了细胞杀伤，表明依赖于代谢。50 μ M双氯亚硝基脲抑制谷胱甘肽还原酶，以前显示增加肝细胞对氧化应激的敏感性，增强对乙酰氨基酚的毒性，而不增加对乙酰氨基酚代谢物的共价结合。用已知降低肝细胞对氧化应激的敏感性的三价铁螯合剂去铁胺预处理肝细胞，在不降低共价结合的情况下防止细胞杀伤。向培养基中加入氯化铁恢复了细胞对对乙酰氨基酚的敏感性，再次对共价结合的程度没有影响。这些数据表明，对乙酰氨基酚的毒性可与其代谢产物的共价结合分离，并支持以下结论：伴随对乙酰氨基酚的混合功能氧化酶依赖性生物转化的氧化应激对肝细胞造成致死性损伤。
Sensitivity of cultured hepatoyctes to acetaminophen was induced by pretreatment of the rat with 3-methylcholanthrene. Under these conditions, 10 uM B-napthoflavone but not SKF-525A prevented the cell killing, indicating dependence on metabolism. Inhibition of glutathione reductase by 50 uM bis-chloronitrosourea, 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 hepatoyctes 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.