title: Effect of halothane on hypoxic toxicity and glutathione status in cultured rat hepatocytes.
abstract: BACKGROUND
  In hypoxic rats, halothane causes hepatotoxicity at oxygen levels that would cause minimal hepatotoxicity in the absence of halothane. Using a model that excludes systemic and extrahepatic effects of halothane, the authors tested the hypothesis that halothane hepatotoxicity in the whole-rat model is caused by a direct hepatotoxic effect of halothane, which is mediated by halothane-derived free radicals.
  
  
  METHODS
  Rat hepatocyte monolayer cultures were exposed to defined gas phases for 2 h. Three experimental variables were present or absent: hypoxia (1% O2), halothane (2%), and cytochrome P-450 induction (by phenobarbital). Two experimental outcomes were measured: aspartate aminotransferase release, a measure of cell death, and reduced glutathione, an endogenous free radical scavenger whose levels are decreased by physiologically significant free radical injury.
  
  
  RESULTS
  As anticipated, hypoxia increased cell death. Cytochrome P-450 induction by itself increased cell death during hypoxia. However, halothane had no effect on cell death during hypoxia, with or without cytochrome P-450 induction. Halothane had no toxic effect, even when glutathione was depleted before the onset of hypoxia. Glutathione was decreased moderately by hypoxia alone. Neither halothane nor cytochrome P-450 induction had any effect on glutathione levels.
  
  
  CONCLUSIONS
  Halothane was not toxic, and it did not generate a physiologically significant free radical insult during hypoxia in the isolated rat hepatocyte under the experimental conditions used in testing.
authors.affiliation: Department of Anesthesiology, Mayo Medical School, Rochester, Minnesota 55905.
authors.forename: M E
authors.initials: ME
authors.lastname: Johnson
authors.forename: J C
authors.initials: JC
authors.lastname: Sill
authors.forename: C B
authors.initials: CB
authors.lastname: Uhl
authors.forename: R A
authors.initials: RA
authors.lastname: Van Dyke
mesh_terms: D000818:Animals; D016923:Cell Death; D015687:Cell Hypoxia / Q000187:drug effects*; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism*; D006221:Halothane / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005978:Glutathione; D006221:Halothane