Ganey P E, Takei Y, Kauffman F C, Thurman R G
Department of Pharmacology, University of North Carolina, Chapel Hill.
Mol Pharmacol. 1990 Dec;38(6):959-64.
Menadione bisulfite is a hepatotoxicant that damages periportal regions of the lobule in perfused liver in an oxygen-dependent manner. The effect of ethanol on menadione bisulfite toxicity was examined in perfused rat liver. Addition of menadione bisulfite (3 mM) alone to the perfusate increased oxygen uptake by 20-30 mumols/g/hr. Lactate dehydrogenase was released into the effluent after 60 min of perfusion and reached values around 100 units/g/hr. Under these conditions, trypan blue was taken up exclusively in periportal regions of the liver lobule; 44% of periportal cells were stained. In the presence of ethanol, maximal increases in oxygen uptake due to menadione bisulfite were much larger (about 90 mumols/g/hr), and lactate dehydrogenase release occurred earlier and reached higher maximal values (330 units/g/hr). Trypan blue staining was also more extensive; 90% of periportal cells were stained. The effect of ethanol on menadione bisulfite-induced oxygen uptake required metabolism via alcohol dehydrogenase (ADH), because ethanol increased oxygen uptake due to menadione bisulfite from 44 to 81 mumols/g/hr in deermice with ADH but had no effect in deermice lacking ADH. Other agents that increase NADH (xylitol and 2-ethyl-1-hexanol) also potentiated the stimulation of oxygen uptake due to menadione bisulfite, suggesting that ethanol was working by increasing the NADH redox state. Cyanide abolished the increase in oxygen uptake due to menadione bisulfite, both in the absence and in the presence of ethanol, supporting the hypothesis that the effect of ethanol on menadione bisulfite-mediated oxygen uptake involves the mitochondrial respiratory chain. Further, the stimulation of oxygen uptake by menadione bisulfite in isolated mitochondria was enhanced when matrix NADH was increased by addition of beta-hydroxybutyrate. These data indicate that ethanol potentiates oxygen uptake and toxicity due to menadione bisulfite most likely by generation of NADH for redox cycling of this model quinone.
亚硫酸氢甲萘醌是一种肝毒性物质，它以氧依赖的方式损害灌注肝脏小叶的门周区域。在灌注大鼠肝脏中研究了乙醇对亚硫酸氢甲萘醌毒性的影响。单独向灌注液中添加亚硫酸氢甲萘醌（3 mM）可使氧摄取增加20 - 30 μmol/g/hr。灌注60分钟后，乳酸脱氢酶释放到流出液中，达到约100单位/g/hr的值。在这些条件下，锥虫蓝仅在肝小叶的门周区域被摄取；44%的门周细胞被染色。在乙醇存在的情况下，亚硫酸氢甲萘醌引起的氧摄取最大增加量要大得多（约90 μmol/g/hr），乳酸脱氢酶释放更早且达到更高的最大值（330单位/g/hr）。锥虫蓝染色也更广泛；90%的门周细胞被染色。乙醇对亚硫酸氢甲萘醌诱导的氧摄取的影响需要通过乙醇脱氢酶（ADH）进行代谢，因为在有ADH的鹿鼠中，乙醇使亚硫酸氢甲萘醌引起的氧摄取从44增加到81 μmol/g/hr，但在缺乏ADH的鹿鼠中没有影响。其他增加NADH的物质（木糖醇和2 - 乙基 - 1 - 己醇）也增强了亚硫酸氢甲萘醌对氧摄取的刺激作用，表明乙醇是通过增加NADH氧化还原状态起作用的。氰化物消除了亚硫酸氢甲萘醌引起的氧摄取增加，无论有无乙醇存在，这支持了乙醇对亚硫酸氢甲萘醌介导的氧摄取的影响涉及线粒体呼吸链的假设。此外，当通过添加β - 羟基丁酸增加基质NADH时，亚硫酸氢甲萘醌对分离线粒体中氧摄取的刺激作用增强。这些数据表明，乙醇最有可能通过生成NADH用于该模型醌的氧化还原循环来增强亚硫酸氢甲萘醌引起的氧摄取和毒性。
