Fraser J M, Kaminsky L S
Toxicol Appl Pharmacol. 1987 Jun 30;89(2):202-10. doi: 10.1016/0041-008x(87)90041-x.
2,2,2-Trifluoroethanol (TFE), the toxic metabolite of the anesthetic agent fluoroxene, is further metabolized to trifluoroacetic acid, which accumulated to maximum serum concentrations 16 to 24 hr after TFE administration to rats. To determine how the metabolic pathways of TFE are related to its toxicity, male Wistar rats were pretreated with various metabolic inhibitors and inducers of cytochrome P-450 metabolism, and TFE toxicity and metabolism were assessed. Pyrazole, disulfiram, isoniazid, diethyldithiocarbamate, and 2-allyl-2-isopropyl-acetamide pretreatment significantly decreased the in vivo metabolism of TFE by 53-100% and decreased the toxicity (as assessed by mortality and leukocyte count alterations). Ethanol induction of rats increased metabolism of TFE by 65% 24 hr after TFE administration but not the toxicity. We conclude that hepatic ethanol-inducible cytochrome P-450 catalyzes the metabolism of most of the TFE but this metabolism is not associated with TFE toxicity, which probably arises by extrahepatic metabolism of TFE by another cytochrome P-450 form.
麻醉剂氟烯的有毒代谢产物2,2,2-三氟乙醇（TFE）会进一步代谢为三氟乙酸，在给大鼠施用TFE后16至24小时，三氟乙酸在血清中的浓度会累积至最高值。为了确定TFE的代谢途径与其毒性之间的关系，对雄性Wistar大鼠进行了各种代谢抑制剂和细胞色素P-450代谢诱导剂的预处理，并评估了TFE的毒性和代谢情况。吡唑、双硫仑、异烟肼、二乙基二硫代氨基甲酸盐和2-烯丙基-2-异丙基乙酰胺预处理可使TFE的体内代谢显著降低53%-100%，并降低毒性（通过死亡率和白细胞计数变化评估）。给大鼠用乙醇诱导后，在施用TFE 24小时后TFE的代谢增加了65%，但毒性并未增加。我们得出结论，肝脏中乙醇诱导型细胞色素P-450催化了大部分TFE的代谢，但这种代谢与TFE毒性无关，TFE毒性可能是由另一种细胞色素P-450形式对TFE进行肝外代谢引起的。
