Younes M, Wagner H, Strubelt O
Institute of Toxicology, Medical University of Lübeck, Federal Republic of Germany.
Biochem Pharmacol. 1989 Oct 15;38(20):3573-81. doi: 10.1016/0006-2952(89)90130-5.
Using isolated hemoglobin-free perfused rat livers we studied the effect of low oxygen supply on ethanol hepatotoxicity in two models. In the first model resembling low blood supply, perfusion rate was lowered from 60 to 10 ml/min after a 30 min-equilibration phase and kept low for 60 min. As a consequence, oxygen consumption fell from 1.76 +/- 0.15 mumol/min/g to 0.51 +/- 0.02 mumol/min/g. In the second model, total ischemia was accomplished by interruption of the perfusion for 30 min and was followed by reperfusion at a perfusion rate of 60 ml/min for a further 30 min. In this model, oxygen consumption returned immediately to normal values upon reperfusion. In both models, low oxygen supply had no toxic effects of its own on livers from fed rats. While ethanol (3 g/l) given under normoxic conditions led to a moderate hepatotoxicity, its application in both models of partial as well as total ischemia and reperfusion resulted in a marked liver damage as evidenced by a strong release of sorbitol dehydrogenase, glutamate-pyruvate-transaminase, lactate dehydrogenase and glutathione, as well as by an increase in hepatic calcium content. Inhibition of ethanol metabolism by 4-methylpyrazol prevented liver damage in both models indicating that metabolism of ethanol is a prerequisite for its toxicity to occur. Also, hepatotoxicity was inhibited partially by catalase and superoxide dismutase and nearly totally by deferrioxamine and allopurinol. Thus, reactive oxygen species which are produced during ethanol metabolism as well as under conditions of low oxygen supply are mediators of hepatic damage in both models employed.
我们使用分离的无血红蛋白灌注大鼠肝脏，在两种模型中研究了低氧供应对乙醇肝毒性的影响。在第一个类似低血供的模型中，经过30分钟的平衡期后，灌注速率从60毫升/分钟降至10毫升/分钟，并保持低灌注60分钟。结果，氧耗量从1.76±0.15微摩尔/分钟/克降至0.51±0.02微摩尔/分钟/克。在第二个模型中，通过中断灌注30分钟实现完全缺血，随后以60毫升/分钟的灌注速率再灌注30分钟。在该模型中，再灌注后氧耗量立即恢复到正常水平。在这两种模型中，低氧供应本身对喂食大鼠的肝脏没有毒性作用。虽然在常氧条件下给予乙醇（3克/升）会导致中度肝毒性，但在部分缺血和完全缺血及再灌注的两种模型中应用乙醇，均导致明显的肝损伤，表现为山梨醇脱氢酶、谷丙转氨酶、乳酸脱氢酶和谷胱甘肽的大量释放，以及肝钙含量增加。4-甲基吡唑对乙醇代谢的抑制作用可预防两种模型中的肝损伤，这表明乙醇代谢是其毒性发生的先决条件。此外，过氧化氢酶和超氧化物歧化酶可部分抑制肝毒性，去铁胺和别嘌呤醇几乎可完全抑制肝毒性。因此，在乙醇代谢过程中以及低氧供应条件下产生的活性氧是所采用的两种模型中肝损伤的介质。
