Leukotriene B4 formation upon halothane-induced lipid peroxidation in liver membrane fractions under low O2 concentrations in vitro.

Lipid peroxidation was induced in rat liver membrane fractions in vitro upon NADPH-dependent metabolic activation of the anesthetic agent halothane at low O2 concentrations. Halothane-induced lipid peroxidation was dependent on time, concentration of halothane, and the calculated O2 concentrations present in the system. Lipid peroxidation was inducible at increasing O2 concentrations up to 12 microM, decreased at higher O2 concentrations up to 48 microM, and was not detectable at normoxic conditions. Leukotriene B4 (LTB4) was identified as a product arising upon lipid peroxidation by reverse-phase high-pressure liquid chromatography combined with a radioimmunoassay. LTB4 formation was maximal under conditions of maximal lipid peroxidation at a calculated O2 concentration of 12 microM. Even at high concentrations, the 5-lipoxygenase inhibitors MK886 (10 microM), ZD2138 (20 microM), and ZM230487 (20 microM) were not inhibitory in halothane-induced lipid peroxidation nor in the associated formation of LTB4. Synthetic LTB4 was transformed into its 20-hydroxy derivative by omega-oxidation in an O2-concentration-dependent manner, being considerably reduced at the low O2 concentrations that maximally promoted lipid peroxidation. The collective evidence of these data raises the possibility that exposure to halothane might lead to peroxidation-associated net synthesis of LTB4 through 5-lipoxygenase-independent escape routes in liver tissue under physiologically or pathophysiologically low O2 concentrations.