Siegers C P, Frühling A, Younes M
Toxicol Appl Pharmacol. 1983 Jun 30;69(2):257-64. doi: 10.1016/0041-008x(83)90306-x.
Halothane hepatotoxicity was observed after exposing hyperthyroid rats to 0.625% halothane for 4 hr under hypoxic conditions (10% O2). In this model, increases in serum enzyme activities of the alanine aminotransferase (GPT) and the sorbitol dehydrogenase (SDH) were evident immediately following exposure and were six-fold higher than in the phenobarbital-hypoxic model. Plasma free-fluoride levels estimated immediately after exposure to halothane were increased twofold in halothane-exposed hyperthyroid rats under hypoxic conditions as were increased twofold in halothane-exposed hyperthyroid rats under hypoxic conditions as compared to a sixfold increase in the phenobarbital-hypoxic model. The concentration of glutathione in liver was more markedly decreased in hyperthyroid rats than in phenobarbital-induced rats. The fact that no clear-cut correlation was found between defluorination and hepatotoxicity in both models may favor the hypothesis that a non-defluorinated metabolite of halothane, e.g., 2-chloro-1,1,1-trifluoroethyl radical, is the reactive intermediate responsible for the liver lesions. On the other hand, intracellular hypoxia due to hypermetabolism during the hyperthyroid state may be the reason for the higher sensitivity of hyperthyroid rats.
在低氧条件（10%氧气）下，将甲状腺功能亢进的大鼠暴露于0.625%的氟烷中4小时后，观察到氟烷肝毒性。在该模型中，暴露后丙氨酸转氨酶（GPT）和山梨醇脱氢酶（SDH）的血清酶活性立即明显升高，比苯巴比妥 - 低氧模型高六倍。与苯巴比妥 - 低氧模型中增加六倍相比，在低氧条件下暴露于氟烷的甲状腺功能亢进大鼠中，暴露于氟烷后立即估计的血浆游离氟水平增加了两倍。甲状腺功能亢进大鼠肝脏中的谷胱甘肽浓度比苯巴比妥诱导的大鼠中更明显降低。在两个模型中均未发现脱氟与肝毒性之间存在明确的相关性，这一事实可能支持这样的假设，即氟烷的一种非脱氟代谢产物，例如2 - 氯 - 1,1,1 - 三氟乙基自由基，是导致肝脏损伤的反应性中间体。另一方面，甲状腺功能亢进状态下由于代谢亢进导致的细胞内低氧可能是甲状腺功能亢进大鼠敏感性较高的原因。
