LEUKOTRIENE B-4 FORMATION UPON HALOTHANE-INDUCED LIPID-PEROXIDATION IN LIVER MEMBRANE-FRACTIONS UNDER LOW O-2 CONCENTRATIONS IN-VITRO

Lipid peroxidation was induced in rat liver membrane fractions in vitr o upon NADPH-dependent metabolic activation of the anesthetic agent ha lothane at low O-2 concentrations. Halothane-induced lipid peroxidatio n was dependent on time, concentration of halothane, and the calculate d O-2 concentrations present in the system. Lipid peroxidation was ind ucible at increasing O-2 concentrations up to 12 mu M, decreased at hi gher O-2 concentrations up to 48 mu M, and was not detectable at normo xic conditions. Leukotriene B-4 (LTB(4)) was identified as a product a rising upon Lipid peroxidation by reverse-phase high-pressure liquid c hromatography combined with a radioimmunoassay. LTB(4) formation was m aximal under conditions of maximal lipid peroxidation at a calculated O-2 concentration of 12 mu M. Even at high concentrations, the 5-lipox ygenase 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 transform ed into its 20-hydroxy derivative by omega-oxidation in an O-2-concent ration-dependent manner, being considerably reduced at the low O-2 con centrations that maximally promoted lipid peroxidation. The collective evidence of these data raises the possibility that exposure to haloth ane might lead to peroxidation-associated net synthesis of LTB(4) thro ugh 5-lipoxygenase-independent escape routes in liver tissue under phy siologically or pathophysiologically low O-2 concentrations.