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.