title: Organic peroxides inhibit neutrophil leukotriene B4 biosynthesis.
abstract: Leukotriene B4, an autacoid metabolite of arachidonic acid produced by polymorphonuclear neutrophils, induces chemokinesis, chemotaxis, and adhesion of these cells at sites of inflammation. Because neutrophil infiltration is a self-limited process, we hypothesized that oxidized lipid products of neutrophil-damaged tissue might inhibit leukotriene B4 biosynthesis, thereby preventing additional neutrophil infiltration and limiting peroxidative tissue damage. Erythrocyte ghosts exposed to a hydrogen peroxide-generating system served as a model of peroxidized tissue in inflammation and inhibited neutrophil leukotriene B4 production by 50% compared with unoxidized ghosts. Organic peroxides, including tert-butylhydroperoxide, peracetic acid, and linoleic hydroperoxide, resembling the product(s) of tissue membrane peroxidation in lipid solubility and catalase resistance, inhibited leukotriene B4 biosynthesis in a dose-dependent manner (50% inhibitory concentration of 3.9 microM compared to 530 microM for H2O2). Biosynthetic steps prior to the 5-lipoxygenase did not appear to be the site of inhibition. Likewise, the step after the 5-lipoxygenase, the leukotriene A4 hydrolase, was not primarily involved. Thus a possible mechanism for controlling the influx of neutrophils and their oxidative damage during inflammation may be inhibition of the 5-lipoxygenase by catalase-resistant lipid peroxides released by tissue membranes.
authors.affiliation: Department of Medicine, Veterans Administration Medical Center, Minneapolis.
authors.forename: I J
authors.initials: IJ
authors.lastname: Okazaki
authors.forename: L M
authors.initials: LM
authors.lastname: Newman
authors.forename: D W
authors.initials: DW
authors.lastname: Allen
mesh_terms: D000217:Acyltransferases / Q000097:blood; D016718:Arachidonic Acid / Q000097:blood; D004910:Erythrocyte Membrane / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood*; D008041:Linoleic Acids / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010463:Peracetic Acid / Q000494:pharmacology*; D010545:Peroxides / Q000494:pharmacology*; D020122:tert-Butylhydroperoxide
chemical_list: D008041:Linoleic Acids; D008054:Lipid Peroxides; D010545:Peroxides; D007975:Leukotriene B4; C008285:linoleic acid hydroperoxide; D016718:Arachidonic Acid; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D000217:Acyltransferases; D010463:Peracetic Acid