Younes M, Strubelt O
Institute of Toxicology, Medical University of Lübeck, FRG.
Pharmacol Toxicol. 1988 Nov;63(5):382-5. doi: 10.1111/j.1600-0773.1988.tb00972.x.
In order to study the events that follow cyanide-induced inhibition of oxidative metabolism and produce cellular injury, isolated, haemoglobin-free perfused rat livers from fasted rats were exposed to KCN (100 mg/l). KCN reduced the oxygen consumption of the livers by about 80%. Hepatotoxicity was evident by a marked release of enzymes (LDH, SDH) and of glutathione (mainly GSSG) into the perfusate, by a depletion of hepatic glutathione and by an accumulation of calcium in the liver. Cyanide-induced hepatotoxicity could be prevented completely by feeding the rats before preparing the liver as well as by addition of fructose to the perfusate of fasted livers. Both treatments resulted in an increased energy supply from anaerobic glycolysis as evidenced by a large release of lactate + pyruvate into the perfusate. The toxic actions of cyanide were markedly attenuated by deferrioxamine as well as by allopurinol. These antitoxic actions occurred without changes in anaerobic glycolysis. Omission of calcium from the perfusate, however, did not influence cyanide toxicity. Thus, energy supply from anaerobic glycolysis seems to be sufficient for the basic functions of the liver to occur, when oxidative metabolism is inhibited by cyanide. The effects of deferrioxamine and allopurinol indicate the involvement of radical intermediates and/or Fe2+ in cyanide-induced cellular toxicity. An influx of calcium from the extracellular to the intracellular space is not involved in cyanide-induced hepatocellular injury.
为了研究氰化物诱导氧化代谢抑制并导致细胞损伤后发生的事件，将禁食大鼠分离得到的无血红蛋白灌注肝脏暴露于KCN（100mg/l）中。KCN使肝脏的氧消耗降低了约80%。肝毒性表现为酶（乳酸脱氢酶、琥珀酸脱氢酶）和谷胱甘肽（主要是氧化型谷胱甘肽）大量释放到灌流液中，肝内谷胱甘肽耗竭以及肝脏中钙的积累。在制备肝脏前给大鼠喂食以及向禁食肝脏的灌流液中添加果糖，均可完全预防氰化物诱导的肝毒性。两种处理均导致无氧糖酵解产生的能量供应增加，这可通过大量乳酸+丙酮酸释放到灌流液中得到证明。去铁胺和别嘌呤醇可显著减轻氰化物的毒性作用。这些解毒作用在无氧糖酵解无变化的情况下发生。然而，从灌流液中去除钙并不影响氰化物的毒性。因此，当氧化代谢被氰化物抑制时，无氧糖酵解提供的能量似乎足以维持肝脏的基本功能。去铁胺和别嘌呤醇的作用表明自由基中间体和/或Fe2+参与了氰化物诱导的细胞毒性。细胞外钙流入细胞内空间不参与氰化物诱导的肝细胞损伤。
