Acute toxicity of fluorinated ether anesthetics: role of 2,2,2-trifluoroethanol and other metabolites.

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.