Potentiation in the intact rat of the hepatotoxicity of acetaminophen by 1,3-bis(2-chloroethyl)-1-nitrosourea.
Potentiation in the intact rat of the hepatotoxicity of acetaminophen by 1,3-bis(2-chloroethyl)-1-nitrosourea.
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1,3-双(2-氯乙基)-1-亚硝基脲在完整大鼠中增强对乙酰氨基酚的肝毒性。
DOI：
10.1016/0003-9861(88)90073-2
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发表时间：
1988
影响因子：
3.9
通讯作者：
Farber,JL
中科院分区：
文献类型：
--
作者：
Nakae,D;Oakes,JW;Farber,JL
对乙酰氨基酚杀死培养的肝细胞的研究表明，细胞受到伴随毒素代谢的氧化应激的伤害(J.L.Farberet al.(1988)Arch。生物化学。生物物理学267、640-650)。本报告证明，扑热息痛杀死培养的肝细胞的基本特征在完整的动物身上重现。雄性大鼠注射扑热息痛1000 mg/kg后24小时未见肝坏死。3-甲基胆蒽诱导的混合功能氧化酶活性增加了对乙酰氨基酚的肝毒性。1，3-二(2-氯乙基)-1-亚硝脲(BCNU)对谷胱甘肽还原酶的抑制增强了对乙酰氨基酚对雄性大鼠的肝毒性。BCNU可使GSH含量降低40%，而用马来酸二乙酯去除GSH并不能增强对乙酰氨基酚的毒性。抗氧化剂二苯二胺(25 mg/kg)和铁络合剂去铁胺(1000 mg/kg)可预防对乙酰氨基酚500 mg/kg所致大鼠肝坏死。两种保护剂都不能阻止对乙酰氨基酚产生的GSH的下降。结论：扑热息痛对培养肝细胞的不可逆性损伤与对乙酰氨基酚在正常大鼠体内的损伤情况并无明显不同。
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. Farberet 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.