Hepatic Necrosis Caused by Halothane and Hypoxia in Phenobarbital-treated Rats

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Abstract
In other studies, hypoxia evidently enhanced the binding of halothane metabolites to components of the hepatic microsomal fraction. Wistar rats were pretreated with phenobarbital, 75 mg/kg, daily for 4 days to induce the hepatic drug-metabolizing enzyme system and subsequently made them hypoxic (FIO2 [fractional concentration of O2 in inspired gas] = .08) while they were receiving halothane, 0.6%. Centrilobular hepatic necrosis was well developed by 6 h following exposure, and early stages of resolution were evident by 48 h. Hemorrhage occurred within the necrotic areas, and leukocytosis was not prominent. Normal rats or those depleted of hepatic glutathione did not experience hepatic necrosis when made hypoxic and given halothane. Rats receiving halothane in adequate oxygen (FIO2 = 0.50) after phenobarbital pretreatment showed no hepatic necrosis. Plasma F- values were normal (< 2 .mu.M) immediately upon completion of halothane exposure when the animals received adequate O2, whether or not they had received phenobarbital pretreatment. When halothane was administered to hypoxic animals, plasma F- values averaged 19 .+-. 2 .mu.M (Mean .+-. [standard error of the mean]), and pretreatment with phenobarbital caused a further increase in plasma F- to 24 .+-. 2 .mu.M. Plasma fluoride values thus increased indicate that the production of defluorinated halothane metabolites is primarily caused by hypoxia. In animals with hepatic necrosis, cytochrome P-450 was decreased but cytochrome b5 was not changed. The selective decrease in cytochrome P-450 suggests a specific, persistent involvement of this enzyme rather than a generalized destruction of microsomal enzymes. Halothane anesthesia causes hepatic necrosis in rats when combined with phenobarbital stimulation of the hepatic drug-metabolizing enzyme system and hypoxia.

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