Rice S A, Maze M, Smith C M, Kosek J C, Mazze R I
Toxicol Appl Pharmacol. 1987 Mar 15;87(3):411-9. doi: 10.1016/0041-008x(87)90246-8.
Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.
雄性Fischer 344大鼠用于研究在常氧条件下（FIO2 = 0.21）异烟肼处理的大鼠暴露于氟烷后的肝脏效应。动物用生理盐水或异烟肼（50 mg/kg）处理7天，然后暴露于1%氟烷或空气中2小时。每个处理和暴露组的一半大鼠在暴露后24小时处死；其余的在暴露后4天处死。氟烷暴露24小时后，与生理盐水处理的大鼠相比，异烟肼处理的大鼠血清转氨酶水平显著升高（即，天冬氨酸转氨酶升高两倍；丙氨酸转氨酶升高七倍）。氟烷暴露使生理盐水处理和异烟肼处理的大鼠胆固醇水平均显著降低。其他指示肝脏和肾脏功能的血清参数无差异：碱性磷酸酶、总蛋白、总胆红素、血细胞比容、尿酸、肌酐、尿素氮、Na+、K+、Ca2+和无机磷酸盐。暴露于空气的生理盐水处理和异烟肼处理的大鼠均未表现出肝脏损伤的组织学证据。然而，暴露于氟烷的大鼠显示出细胞形态的局限性破坏。在异烟肼处理的动物中观察到最严重的病变，有广泛的中央周围肝细胞坏死以及白细胞和库普弗细胞浸润。与生理盐水处理的大鼠相比，异烟肼处理的大鼠血清中氟烷氧化代谢的两种产物三氟乙酸和溴的浓度显著升高。还原代谢产物氟的血清水平无差异。这些结果强烈表明，氟烷给药后的肝损伤可能由氧化代谢中间体产生。
