Murphy M J, Dunbar D A, Kaminsky L S
Toxicol Appl Pharmacol. 1983 Oct;71(1):84-92. doi: 10.1016/0041-008x(83)90047-9.
The fluorinated ethers 2,2,2-trifluoroethyl vinyl ether (TFVE), 2,2,2-trifluoroethyl ethyl ether (TFEE), and 2,2,2-trifluoroethyl allyl ether (TFAE) are lethal to rats pretreated with a variety of cytochrome P-450-inducing agents at doses not toxic to uninduced rats. The hepatic microsomal cytochrome P-450-catalyzed metabolic pathways have been elucidated: TFVE yields 2,2,2-trifluoroethanol (TFE) and glycolaldehyde; TFEE yields TFE and acetaldehyde; and TFAE yields TFE and acrolein. Time courses of metabolite concentrations in blood after administration of toxic doses of metabolites or anesthetics to variously induced rats were compared. For TFVE, phenobarbital (PB) or pregnenolone-16 alpha-carbonitrile (PCN) induction increased acute lethality 3.1- and 2.4-fold respectively, and blood TFE concentrations reached lethal levels. beta-Naphthoflavone (BNF) induction did not produce lethality and TFE concentrations did not reach lethal levels. Glycolaldehyde concentrations did not approximate lethal levels in any case. For TFEE, PB, BNF, or PCN induction increased lethality 3.4-, 2.6-, and 2.0-fold respectively, and TFE concentrations exceeded lethal levels in all cases. Acetaldehyde concentrations did not approximate lethal levels in any case. For TFAE, BNF, or PCN induction increased lethality 3.2- and 4.6-fold respectively, and TFE concentrations approached lethal levels. PB induction did not produce lethality nor did TFE concentrations reach lethal levels. Blood acrolein concentrations could not be determined. Thus the lethal effects of the three anesthetics arise from specific cytochrome P-450 isozyme-catalyzed metabolism to TFE. The relative rates of formation of TFE from the three anesthetics, catalyzed by microsomes from untreated and variously induced rats, supported this conclusion.
氟化醚2,2,2 - 三氟乙基乙烯基醚（TFVE）、2,2,2 - 三氟乙基乙醚（TFEE）和2,2,2 - 三氟乙基烯丙基醚（TFAE），对于经多种细胞色素P - 450诱导剂预处理的大鼠具有致死性，其剂量对未诱导的大鼠无毒。已经阐明了肝微粒体细胞色素P - 450催化的代谢途径：TFVE产生2,2,2 - 三氟乙醇（TFE）和乙醇醛；TFEE产生TFE和乙醛；TFAE产生TFE和丙烯醛。比较了向不同诱导状态的大鼠给予毒性剂量的代谢产物或麻醉剂后，血液中代谢产物浓度随时间的变化过程。对于TFVE，苯巴比妥（PB）或孕烯醇酮 - 16α - 腈（PCN）诱导分别使急性致死率提高3.1倍和2.4倍，血液中TFE浓度达到致死水平。β - 萘黄酮（BNF）诱导未产生致死性，TFE浓度未达到致死水平。在任何情况下，乙醇醛浓度都未接近致死水平。对于TFEE，PB、BNF或PCN诱导分别使致死率提高3.4倍、2.6倍和2.0倍，并且在所有情况下TFE浓度都超过了致死水平。在任何情况下，乙醛浓度都未接近致死水平。对于TFAE，BNF或PCN诱导分别使致死率提高3.2倍和4.6倍，TFE浓度接近致死水平。PB诱导未产生致死性，TFE浓度也未达到致死水平。血液中丙烯醛浓度无法测定。因此，这三种麻醉剂的致死作用源于特定细胞色素P - 450同工酶催化代谢生成TFE。由未处理和不同诱导状态的大鼠的微粒体催化的这三种麻醉剂生成TFE的相对速率支持了这一结论。
