Rao G S
J Med Chem. 1977 Feb;20(2):262-5. doi: 10.1021/jm00212a015.
Various anesthetic and nonanesthetic doses of [1-14C]halothane were administered separately to normal and phenobarbital-pretreated (PBP) rats by ip route. The rats were sacrificed at 0.5-24 h after dosing, and livers were removed and examined histopathologically for tissue necrosis. Only PBP rats that received anesthetic doses of halothane (11.5 or 23 mmol/kg) and sacrificed 24 h after dosing exhibited liver toxicity. Determination of the radioactivity distribution among various liver macromolecules revealed that the protein fraction contained the highest activity at all time points in all animals. The lipid fraction showed some radioactivity during the initial 1-6 h period which disappeared after 6-8 h, while the DNA fraction was devoid of radioactivity in all animals injected with [14C]halothane. All the PBP rats that exhibited liver necrosis consistently attained higher covalent binding of halothane metabolites to liver proteins (2.13-2.20 nmol/mg of protein) when compared with the protein binding (1.12-1.41 nmol/mg of protein) observed among the rats that did not exhibit liver toxicity during the same time period. These results suggest a correlation between covalent binding of halothane metabolites to liver proteins and halothane-induced liver necrosis.
将不同麻醉剂量和非麻醉剂量的[1-¹⁴C]氟烷分别经腹腔注射给予正常大鼠和经苯巴比妥预处理（PBP）的大鼠。给药后0.5至24小时处死大鼠，取出肝脏并进行组织病理学检查以确定组织坏死情况。只有接受麻醉剂量氟烷（11.5或23 mmol/kg）并在给药后24小时处死的PBP大鼠表现出肝脏毒性。对各种肝脏大分子中放射性分布的测定表明，在所有动物的所有时间点，蛋白质部分的活性最高。脂质部分在最初1至6小时内显示出一些放射性，在6至8小时后消失，而在所有注射[¹⁴C]氟烷的动物中，DNA部分均无放射性。与在同一时间段内未表现出肝脏毒性的大鼠中观察到的蛋白质结合（1.12至1.41 nmol/mg蛋白质）相比，所有表现出肝脏坏死的PBP大鼠中，氟烷代谢产物与肝脏蛋白质的共价结合始终更高（2.13至2.20 nmol/mg蛋白质）。这些结果表明氟烷代谢产物与肝脏蛋白质的共价结合和氟烷诱导的肝脏坏死之间存在相关性。
