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 halo thane. Using a model that excludes systemic and extrahepatic effects o f halothane, the authors tested the hypothesis that halothane hepatoto xicity in the whole-rat model is caused by a direct hepatotoxic effect of halothane, which is mediated by halothane-derived free radicals Me thods: Rat hepatocyte monolayer cultures were exposed to defined gas p hases for 2 h. Three experimental variables were present or absent: hy poxia (1% O2), halothane (2%), and cytochrome P-450 induction (by phen obarbital). Two experimental outcomes were measured: aspartate aminotr ansferase release, a measure of cell death, and reduced glutathione, a n endogenous free radical scavenger whose levels are decreased by phys iologically significant free radical injury. Results. As anticipated, hypoxia increased cell death. Cytochrome P-450 induction by itself inc reased 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 bef ore the onset of hypoxia. Glutathione was decreased moderately by hypo xia alone. Neither halothane nor cytochrome P-450 induction had any ef fect 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 c onditions used iii testing.