An Animal Model of Halothane Hepatotoxicity: Roles of Enzyme Induction and Hypoxia
An Animal Model of Halothane Hepatotoxicity: Roles of Enzyme Induction and Hypoxia
复制标题
氟烷肝毒性动物模型：酶诱导和缺氧的作用
作者：
G. McLain;I. Sipes;B. R. Brown
将苯巴比妥预处理的雄性 Sprague-Dawley 大鼠在缺氧条件下（Fl02 0.14）暴露于 1% 氟烷中两小时，导致 24 小时内出现广泛的小叶中心坏死。伴随形态学损伤的是血清谷氨酸丙酮酸转氨酶 (SGPT) 增加和肝微粒体细胞色素 P-450 减少。肝脏中的谷胱甘肽水平没有变化。苯巴比妥预处理的大鼠在 FI02 0.21 下用 1% 氟烷麻醉，24 小时后仅出现轻微的形态变化。在任何非苯巴比妥诱导的大鼠或暴露于F102 0.10的乙醚或暴露于F102 0.99的氟烷的任何诱导的动物中均未出现肝损伤。在发生广泛的小叶中心坏死的大鼠中，24小时尿液中氟化物的排泄量增加了2.6倍。当对苯巴比妥诱导的维持低氧（FI02 0.14）的大鼠腹膜内施用14C-氟烷两小时时，14C-氟烷与14C脂质的体内共价结合也显着增加。这些结果支持作者的假设，即氟烷通过还原性或非氧依赖性细胞色素 P-450 依赖性途径代谢为肝毒性中间体。这种氟烷诱导的肝毒性动物模型可能具有临床相关性。氟烷麻醉期间肝血流量减少可能会减少肝细胞可用的 P02，从而引导氟烷沿着其还原性肝毒性途径代谢。
Exposure of phenobarbital-pretreated male Sprague-Dawley rats to halothane, 1 per cent, for two hours under conditions of hypoxia (Fl02 0.14) resulted in extensive centrilobular necrosis within 24 hours. Accompanying the morphologic damage were an increase in serum glutamic pyruvic transminase (SGPT) and a decrease in hepatic microsomal cytochrome P-450. Glutathione levels in the liver were unchanged. Phenobarbital-pretreated rats anesthetized with halothane, 1 per cent, at FI02 0.21 had only minor morphologic changes at 24 hours. Hepatic injury was not appearent in any non-phenobarbital-induced rat or in any induced animal exposed to ether at Fl02 0.10 or to halothane at Fl02 0.99. There was a 2.6-fold increase in the 24-hour urinary excretion of fluoride in those rats in which extensive centrilobular necrosis developed. The in-vivo covalent binding to lipids of 14C from 14C-halothane also was increased markedly when 14C-halothane was administered intraperitoneally to phenobarbital-induced rats maintained hypoxic (FI02 0.14) for two hours. These results support the authors' hypothesis that halothane is metabolized to hepatotoxic intermediates by a reductive or non-oxygen-dependent cytochrome P-450-dependent pathway. This animal model of halothane-induced hepatotoxicity may be clinically relevant. A decrease in hepatic blood flow during halothane anesthesia may decrease the P02 available to hepatocytes and thus direct the metabolism of halothane along its reductive, hepatotoxic pathway.