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.

Trifluorinated ether anesthetic lethality in rats: the role of bacterial infection.

The lethal effects of the fluorinated ether anesthetics fluroxene (2,2,2-trifluoroethyl vinyl ether) and its ethyl (TFEE) and allyl analogues in male Wistar rats have previously been demonstrated to be potentiated by specific hepatic microsomal cytochromes P-450, and mediated by the common metabolite 2,2,2-trifluoroethanol (TFE). We report here that administration of lethal combinations of anesthetic and cytochrome P-450-inducing agents or of lethal doses of TFE (0.21 g/kg and higher) to rats caused decreased white blood cell counts, necrosis of sternum bone marrow cells and lymphocytes in the thymic cortex, and resulted in Escherichia coli contamination of the blood, lungs, liver, and kidneys of treated rats. Control animals in identical environments were free of bacterial contamination. Pretreatment of rats with the antibiotic tetracycline-HCl in the drinking water (0.6 g/liter) from 24 hr before anesthetic or TFE administration significantly diminished the mortality. With TFEE and beta-naphthoflavone induction, mortality was reduced from 85 to 30% by the antibiotic. However, the antibody plaque assay following immunization with sheep erythrocytes indicated that the primary humoral immune response to a thymus-dependent antigen was not impaired in treated rats. These results considered together indicate that metabolic formation of TFE from the anesthetic agents produced a decreased host resistance with subsequent increased susceptibility to bacterial infection. If not administered the antibiotic, the animals succumbed to the infection.

Enzymic reactions of fatty acid hydroperoxides in extracts of potato tuber. I. Comparison 9D- and 13L-hydroperoxy-octadecadienoic acids as substrates for the formation of a divinyl ether derivative.

1. 9-D-Hydroperoxy-octadeca-trans-10, cis-12-dienoic acid (formed from linoleic acid by potato lipoxygenase) is enzymically converted to a divinyl ether derivative (colneleic acid) by extracts of potato tuber. 2. the isomeric 13-L-hydroperoxide (formed from linoleic acid by soyabean lipoxygenase) is not a substrate for this enzyme system. 3. the enzyme reaction was not dependent on oxygen and was unaffected by metal chelators and thiol reagents. 4. studies with 18O-labelled substrate indicate that the ether oxygen atom in colneleic acid is not derived from the oxygens of the hydroperoxide group.

An investigation into the hepatic cytochrome P-450 catalysed metabolism of the anaesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether).

The role of the different cytochromes P-450 in the metabolism of the anaesthetic agent fluroxene, and the mechanism of production of toxic effects seen after pre-treatment of the animals with pehnobarbital prior to anaesthesia, have been investigated. Male rats were anaesthetized with fluroxene, or with 2,2,2-trifluroethyl ethyl ether, or with ethyl vinyl ether in an attempt to ascertain the in vivo toxic effects of the three anaesthetic agents. The resultant hepatic histology is reported. A study of the binding and metabolism of fluroxene by isolated rat hepatic microsomes was also made. We conclude that it is elevated levels of cytochrome P-450 which potentiate the toxicity of fluroxene anaesthesia in phenobarbital treated animals and that cytochrome P-448 does not bind or metabolize fluroxene. The potential toxicity of the fluroxene molecule is considered to reside in the trifluoroethyl moiety, while the vinyl group of fluroxene appears to play a role in the observed liver damage.