Demonstration of halothane-induced hepatic lipid peroxidation in rats by quantification of F-2-isoprostanes

Background: Halothane can be reductively metabolized to free radical intermediates that may initiate lipid peroxidation. Hypoxia and phenobarbital pretreatment in Sprague-Dawley rats increases reductive metabolism of halothane. F-2-isoprostanes, a novel measure of lipid peroxidation in vivo, were used to quantify halothane-induced lipid peroxidation in rats. Methods: Rats were exposed to 1% halothane at 21% or 14% O-2 for 2 h. Pretreatments included phenobarbital, isoniazid, or vehicle. Rats also were exposed to halothane, enflurane, and desflurane at 21% O-2. Lipid peroxidation was assessed by mass spectrometric quantification of F-2-isoprostanes. Results: Exposure of phenobarbital-pretreated rats to 1% halothane at 21% O-2 for 2 h caused liver and plasma F-2-isoprostane concentrations to increase fivefold compared to nonhalothane control rats. This halothane-induced increase was enhanced by 14% O-2, but hypoxia alone had no significant effect. Alanine aminotransferase activity at 24 h was significantly increased only in the 1% halothane/14% O-2 group. The effect of cytochrome P450 enzyme induction on halothane-induced F-2-isoprostane production and liver injury was determined by comparing the effects of isoniazid and phenobarbital pretreatment with no pretreatment under hypoxic conditions. Halothane caused 4- and 11-fold increases in plasma and liver F-2-isoprostanes, respectively, in non-pretreated rats, whereas isoniazid pretreatment had no effect. Phenobarbital pretreatment potentiated halothane-induced lipid peroxidation with 9- and 20-fold increases in plasma and liver F-2-isoprostanes, respectively. Alanine aminotransferase activity was increased only in this group. At ambient oxygen concentrations, halothane but not enflurane or desflurane, caused F-2-isoprostanes to increase. Conclusions: Specific halothane-Induced lipid peroxidation was demonstrated in Sprague-Dawley rats using quantification of F-2-isoprostanes and was Increased by hypoxia and phenobarbital pretreatment, but not isoniazid pretreatment.