Younes M, Strubelt O
Biochem Pharmacol. 1987 Sep 15;36(18):2973-7. doi: 10.1016/0006-2952(87)90211-5.
Using isolated hemoglobin-free perfused rat livers we investigated the hepatotoxic effects of hypoxia, ethanol or the combination of both. Hypoxia only (90 min) led to a weak toxicity as evidenced by the efflux of the enzymes glutamate-pyruvate-transaminase (GPT) and sorbitol dehydrogenase (SDH). This toxic effect was slightly higher in livers treated with ethanol (3 g/l) under normoxic conditions. Ethanol added under hypoxic conditions, however, showed a strong hepatotoxic effect. Under hypoxic conditions, lactate + pyruvate production was increased fivefold over control, indicating that glycolysis was more effectively undergone as main source of energy. Addition of ethanol suppressed this effect, indicating that ethanol inhibited glycolysis. These results indicate that ethanol potentiates hypoxic liver damage by inhibiting the main metabolic pathway yielding ATP under low oxygen tension resulting in a severe energy deficit. Allopurinol (100 mg/l) inhibited the toxic effects seen with ethanol + hypoxia. Also, the inhibitory action of ethanol on glycolysis was antagonized. Our results are consistent with the following model: hypoxia converts NAD-dependent xanthine dehydrogenase (XD) into the oxygen-dependent xanthine oxidase (XO). Due to hypoxia and ethanol, purine metabolites and acetaldehyde accumulate and are metabolized via XO. This process leads to the production of oxygen radicals which most probably mediate both the inhibition of glycolysis and the direct toxic effects towards liver cells.
我们使用分离的无血红蛋白灌注大鼠肝脏，研究了缺氧、乙醇或二者联合的肝毒性作用。仅缺氧（90分钟）导致轻微毒性，如谷氨酸丙酮酸转氨酶（GPT）和山梨醇脱氢酶（SDH）的流出所示。在常氧条件下用乙醇（3 g/l）处理的肝脏中，这种毒性作用略高。然而，在缺氧条件下添加乙醇则显示出强烈的肝毒性作用。在缺氧条件下，乳酸+丙酮酸的产生比对照增加了五倍，表明糖酵解作为主要能量来源更有效地进行。添加乙醇抑制了这种作用，表明乙醇抑制了糖酵解。这些结果表明，乙醇通过抑制低氧张力下产生ATP的主要代谢途径，增强了缺氧性肝损伤，导致严重的能量缺乏。别嘌呤醇（100 mg/l）抑制了乙醇+缺氧时所见的毒性作用。此外，乙醇对糖酵解的抑制作用也被拮抗。我们的结果与以下模型一致：缺氧将依赖NAD的黄嘌呤脱氢酶（XD）转化为依赖氧的黄嘌呤氧化酶（XO）。由于缺氧和乙醇，嘌呤代谢产物和乙醛积累并通过XO代谢。这个过程导致氧自由基的产生，氧自由基很可能介导了糖酵解的抑制和对肝细胞的直接毒性作用。
