A Possible Mechanism of Toxicity of Trifluoroethanol and Other Halothane Metabolites

Several drugs modify the lethal action of trifluoroethanol (TFE) and trifluoroacetaldehyde hydrate (TFA1H). The toxic effect of these metabolites of halothane may be due to the reactions of trifluoroacetaldehyde (TFA1), since the toxicity of TFE was reduced by the administration of ethanol (500 mg/kg × 2, intraperitoneally) or 4-iodo-pyrazole (50 mg/kg × 2, intraperitoneally), an inhibitor of alcohol dehydrogenase. Furthermore, allopurinol (20 mg/kg × 2, intraperitoneally), which as an inhibitor of xanthine oxidase may decrease the further oxidation of TFA1, increased the toxicity of TFE and TFA1H but not that of trifluoroacetic acid (TFAA). Isoniazid (50 mg/kg × 2, intraperitoneally), a carbonyl reagent, effectively reduced the toxicity of TFE and TFA1H, while cysteine (500 mg/kg × 2, intraperitoneally) showed some protection against the TFE toxicity. Cysteine, in vitro, also prevented the inhibitory action of TFA1H and TFAA on the creatine phosphokinase (CPK) activity. TFE did not inhibit this SH-enzyme in vitro. Thus the formation of a thiol-binding aldehyde may be essential for the metabolic blocking effect and toxicity of TFE and TFA1H.