Nakae D, Oakes J W, Farber J L
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Arch Biochem Biophys. 1988 Dec;267(2):651-9. doi: 10.1016/0003-9861(88)90073-2.
Studies of the killing of cultured hepatocytes by acetaminophen indicate that the cells are injured by an oxidative stress that accompanies the metabolism of the toxin (J. L. Farber et al. (1988) Arch. Biochem. Biophys. 267, 640-650). The present report documents that the essential features of the killing of cultured hepatocytes by acetaminophen are reproduced in the intact animal. Male rats had no evidence of liver necrosis 24 h after administration of up to 1000 mg/kg of acetaminophen. Induction of mixed function oxidase activity by 3-methylcholanthrene increased the hepatotoxicity of acetaminophen. Inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) potentiated the hepatotoxicity of acetaminophen in male rats induced with 3-methylcholanthrene. Whereas the pretreatment with BCNU reduced the GSH content by 40%, a comparable depletion of GSH by diethylmaleate did not potentiate the toxicity of acetaminophen. The antioxidant diphenylphenylenediamine (25 mg/kg) and the ferric iron chelator deferoxamine (1000 mg/kg) prevented the liver necrosis produced by 500 mg/kg acetaminophen in rats pretreated with BCNU. Neither protective agent prevented the fall in GSH produced by acetaminophen. It is concluded the conditions of the irreversible injury of cultured hepatocytes by acetaminophen previously reported are not necessarily different from those that obtain in the intact rat with this toxin.
对乙酰氨基酚对培养肝细胞杀伤作用的研究表明，细胞受到伴随该毒素代谢产生的氧化应激损伤（J. L. 法伯等人，（1988年）《生物化学与生物物理学报》267卷，640 - 650页）。本报告证明，对乙酰氨基酚对培养肝细胞杀伤作用的基本特征在完整动物中也会重现。雄性大鼠给予高达1000毫克/千克对乙酰氨基酚24小时后，未出现肝坏死迹象。用3 - 甲基胆蒽诱导混合功能氧化酶活性可增加对乙酰氨基酚的肝毒性。1,3 - 双（2 - 氯乙基）- 1 - 亚硝基脲（BCNU）抑制谷胱甘肽还原酶可增强3 - 甲基胆蒽诱导的雄性大鼠对对乙酰氨基酚的肝毒性。虽然用BCNU预处理使谷胱甘肽（GSH）含量降低了40%，但用马来酸二乙酯使GSH产生类似程度的耗竭并未增强对乙酰氨基酚的毒性。抗氧化剂二苯基苯二胺（25毫克/千克）和铁螯合剂去铁胺（1000毫克/千克）可预防用BCNU预处理的大鼠中500毫克/千克对乙酰氨基酚所致的肝坏死。两种保护剂均未阻止对乙酰氨基酚导致的GSH含量下降。得出的结论是，先前报道的对乙酰氨基酚对培养肝细胞不可逆损伤的条件不一定与该毒素在完整大鼠中的情况不同。
