Effect of halothane on hypoxic toxicity and glutathione status in cultured rat hepatocytes.
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.
Johnson
M E
ME
Department of Anesthesiology, Mayo Medical School, Rochester, Minnesota 55905.
Sill
J C
JC
Uhl
C B
CB
Van Dyke
R A
RA
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
D005978:Glutathione; D006221:Halothane