Effect of Halothane on Hypoxic Toxicity and Glutathione Status in Cultured Rat Hepatocytes

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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 wholerat model is caused by a direct hepatotoxic effect of halothane, which is mediated by halothane-derived free radicals.


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.


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 hypocia alone. Neither halothane nor cytochrome P-450 induction had any effect on glutathione levels.


Halothane was not toxic, and it did not generate a physiologically significant free radical insult during hypoxia in the isolated rat hepatocyte under the experinmental conditions used in testing.

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