The role of cytochrome P-450 in the toxicity of fluroxene (2,2,2-trifluoroethyl vinyl ether) anaesthesia in vivo.

Induction of type P-450 cytochromes in rats by i.p. injections of phenobarbital potentiated the toxicity (100% mortality) of the normally non-toxic anaesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether). The toxic effects were eliminated by administration of 2-allyl-2-isopropylacetamide prior to anaesthesia. Hepatic microsomal cytochrome P-450 levels of the dead rats were markedly diminished relative to unanaesthetised induced controls. Induction by 3-methylcholanthrene and 3,4-benzpyrene did not potentiate toxic effects of fluroxene but anaesthesia after mixed induction with 3-methylcho-lanthrene and phenobarbital manifested toxicity more rapidly than induction with phenobarbital alone. When 2,2,2-trifluoroethyl ethyl ether was used as the anaesthetic similar toxic effects were observed except that levels of type P-450 cytochromes were not depressed at the time of death and induction with 3-methylcholanthrene did potentiate toxic effects with this anaesthetic. We interpret these results to indicate that cytochrome P-450 catalyses an essential step in the production of toxic metabolites from fluroxene and that elevated concentrations of the enzyme are required to potentiate the toxicity. Apparently, cytochrome P-448 does not metabolize fluroxene and elevated levels of this enzyme therefore do not potentiate the toxicity of fluroxene anaesthesia. The ability of fluroxene to destroy cytochrome P-450 resides in its vinyl group while the toxic metabolite arises from the trifluoroethyl moiety.