Glutathione Depletion Following Inhalation Anesthesia

Zumbiel, Margaret A.; Fiserova-Bergerova, Vera; Malinin, Theodore I.; Holaday, Duncan A.

doi:10.1097/00000542-197808000-00009

Cited by 20 publications

(16 citation statements)

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“…In pretreated animals the fluorine concentrations were significantly greater than in nonpretreated animals. The same observation was made in similar experiments in mice (19,20). After exposure, the amount of fluorinated compound in all tissues of pretreated mice (except in the liver) kept increasing up to 10 hr, the maximal survival time (Fig.…”

Section: Metabolites Of Fluroxenesupporting

confidence: 80%

“…In gross examination, no apparent changes in organs were observed. Histological examination showed hepatocellular changes, predominantly centrolobular vacuolization, moderate fatty metamorphosis, passive hyperemia, and sinusoidal congestion (19). Similar hepatotoxicity was observed in rats, but the fluroxene anesthesia was not fatal (11).…”

Section: Metabolites Of Fluroxenesupporting

confidence: 53%

“…The effects of drugs on toxicity of fluroxene and its metabolites are summarized in Table 3. During and following fluroxene exposure, glutathione was profoundly depleted in blood and tissues of mice and rats (the depletion in mice was more extensive) and slightly depleted in blood of anesthetized monkeys (19). No depletion in human blood was observed (Our unpublished observation; tissues of monkeys and man were not examined).…”

Section: Toxicity Of Fluroxene Metabolitesmentioning

confidence: 94%

“…After exposure, the amount of fluorinated compound in all tissues of pretreated mice (except in the liver) kept increasing up to 10 hr, the maximal survival time (Fig. 1 Toxicity of Fluroxene Fluroxene has been found to be highly toxic to mice (7,12,(18)(19)(20)22), dogs, cats, and rabbits (8, 23), but not to man (1,8,15 (7), and sex (18). In mice fluroxene is more toxic in males than in females.…”

Section: Metabolites Of Fluroxenementioning

confidence: 99%

“…Administration of sex hormones reverses the fluroxene toxicity in male and female mice (18) Death resulting from fluroxene anesthesia may be delayed for 6 hr if the mice are simultaneously treated with L-cysteine (19).…”

Section: Modification Of Fluroxene Toxicity By Other Drugsmentioning

confidence: 99%

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Metabolism and Toxicity of 2,2,2-Trifluoroethyl Vinyl Ether

Fiserova-Bergerova¹

1977

Environmental Health Perspectives

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A review on metabolism and toxicity of the fluorinated anesthetic agent, fluroxene, is presented. Fluroxene anesthesia is nontoxic to man but fatal to many experimental animals. The fluroxene molecule (2,2,2-trifluoroethyl vinyl ether) is composed of two moieties; both are toxic as a result of their metabolism: the vinyl moiety destroys heme of cytochrome P-450 while being metabolized to the final product, CO2. The trifluoroethyl moiety is oxidized to trifluoroethanol (TFE) and trifluoroacetic acid (TFAA), and the acute toxicity of fluroxene is related to this pathway. The ratio of metabolites (TFAA to TFE) excreted by different species exposed to fluroxene varies; whenever highly toxic TFE is the major metabolite, fluroxene toxicity is high (rodents, dogs, phenobarbital pretreated monkeys), whenever TFAA is the major metabolite (man, monkey) fluroxene is not toxic. Toxicity in different species also correlates with the extent of glutathione depletion following fluroxene exposure.Fluroxene metabolism and toxicity are modified by drugs metabolized by or affecting the activity of the microsomal cytochrome P-450-system or enzymes involved in ethanol metabolism. The susceptibility of fluroxene to two enzymatic systems which are modified by environmental and genetic factors may explain the large differences in fluroxene toxicity to various species. The fate of one-third of fluroxene administered to man remains unknown.Trifluoroethyl vinyl ether, fluroxene, was introduced in 1953 as the first fluorinated inhalation anesthetic (1), under the trade name Fluoromar. It is slightly flammable, but was considered to be an anesthetic agent of high clinical safety. In 1975, after enflurane had appeared on the market, the manufacture of fluroxene was discontinued. The 22-year history of fluroxene (Table 1) is an interesting one. During this period, fluroxene was found to be toxic to surgical patients in only four cases, and in these four cases other medications were involved (9, 10, 13, 14). As good as this record is, fluroxene would never have been approved for use in humans if it had to undergo present-day testing standards, because it happens to be highly toxic to experimental animals (recognized in 1972) (7) and is extensively metabolized to highly toxic metabolites (discovered in 1967) (5). Metabolites of FluroxeneWhen labeled fluroxene was injected into mice and dogs, trifluoroacetic acid (TFAA) and tri-

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Section: Metabolites Of Fluroxenesupporting

confidence: 80%

Section: Metabolites Of Fluroxenesupporting

confidence: 53%

Section: Toxicity Of Fluroxene Metabolitesmentioning

confidence: 94%