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 O-2 concentrations. Halothane-induced lipid peroxidation was dependent on time, concentration of halothane, and the calculated O-2 concentrations present in the system. Lipid peroxidation was inducible at increasing O-2 concentrations up to 12 mu M, decreased at higher O-2 concentrations up to 48 mu M, and was not detectable at normoxic conditions. Leukotriene B-4 (LTB(4)) was identified as a product arising upon Lipid peroxidation by reverse-phase high-pressure liquid chromatography combined with a radioimmunoassay. LTB(4) formation was maximal under conditions of maximal lipid peroxidation at a calculated O-2 concentration of 12 mu M. Even at high concentrations, the 5-lipoxygenase inhibitors MK886 (10 mu M), ZD2138 (20 mu M), and ZM230487 (20 mu M) were not inhibitory in halothane-induced lipid peroxidation nor in the associated formation of LTB(4). Synthetic LTB(4) was transformed into its 20-hydroxy derivative by omega-oxidation in an O-2-concentration-dependent manner, being considerably reduced at the low O-2 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 LTB(4) through 5-lipoxygenase-independent escape routes in liver tissue under physiologically or pathophysiologically low O-2 concentrations.