PATHOPHYSIOLOGICAL CONSEQUENCES OF ENHANCED INTRACELLULAR SUPEROXIDE FORMATION IN ISOLATED PERFUSED-RAT-LIVER
PATHOPHYSIOLOGICAL CONSEQUENCES OF ENHANCED INTRACELLULAR SUPEROXIDE FORMATION IN ISOLATED PERFUSED-RAT-LIVER
复制标题
DOI：
10.1016/0009-2797(92)90120-a
复制
发表时间：
1992-09-14
影响因子：
5.1
通讯作者：
BENZICK, AE
中科院分区：
文献类型：
--
作者：
JAESCHKE, H;BENZICK, AE
在雄性Fischer大鼠离体灌注肝脏中研究了增强细胞内活性氧形成的潜在毒性。灌注液中氧化还原循环剂敌草快（200 μ M）的存在增加了谷胱甘肽二硫化物（GSSG）进入胆汁的基础流出量（2.65 +/- 0.26 nmol GSH当量/min/g肝重量）。和灌注液（0.55 +/-0.15nmol/min/g）约10倍。由于未发现GSSG在这些动物的胆道中降解的证据，因此可以估计敌草快诱导恒定的O2产生，约为1000 nmol/min/g肝脏重量，持续1小时。因此，在这些条件下的活性氧形成比在各种病理生理条件下高1 - 2个数量级。仅观察到轻微肝损伤（乳酸脱氢酶活性释放）。为了增加肝脏对氧化应激的敏感性，动物在体内用200 mg/kg体重进行预处理。佛尔酮，其引起肝谷胱甘肽含量的90%消耗，100 mg/kg硫酸亚铁，佛尔酮和硫酸亚铁的组合，或40 mg/kg BCNU，其引起肝GSSG还原酶的60%抑制。只有佛尔酮+硫酸亚铁或BCNU联合用药才能显著增加敌喹引起的肝损伤。我们的研究结果表明，肝脏对细胞内活性氧形成的抵抗力极高（即使解毒系统受损），可以作为评估活性氧对各种疾病状态下肝损伤的潜在贡献的参考。
The potential toxicity of enhanced intracellular reactive oxygen formation was investigated in isolated perfused livers of male Fischer rats. The presence of the redox-cycling agent diquat in the perfusate (200 muM) increased the basal efflux of glutathione disulfide (GSSG) into bile (2.65 +/- 0.26 nmol GSH-equivalents/min per g liver wt.) and perfusate (0.55 +/- 0.15 nmol/min per g) approximately 10-fold. Since no evidence was found for degradation of GSSG in the biliary tract of these animals, it could be estimated that diquat induced a constant O2- approximately generation of approximately 1000 nmol/min per g liver wt for 1 h. Thus, reactive oxygen formation under these conditions was 1 - 2 orders of magnitude higher than under various pathophysiological conditions. Only minor liver injury (release of lactate dehydrogenase activity) was observed. To increase the susceptibility of the liver to the oxidant stress, animals were pretreated in vivo with 200 mg/kg body wt. phorone, which caused a 90% depletion of the hepatic glutathione content, 100 mg/kg ferrous sulfate, a combination of phorone and ferrous sulfate, or 40 mg/kg BCNU, which caused a 60% inhibition of hepatic GSSG reductase. Only the combined treatment of phorone + ferrous sulfate or BCNU caused a significant increase of the diquat-induced liver injury. Our results demonstrated an extremely high resistance of the liver against intracellular reactive oxygen formation (even with impaired detoxification systems) and can serve as reference for the evaluation of potential contributions of reactive oxygen to liver injury in various disease states.