THE SELENOENZYME PHOSPHOLIPID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE CONTROLS THE ACTIVITY OF THE 15-LIPOXYGENASE WITH COMPLEX SUBSTRATES ANDPRESERVES THE SPECIFICITY OF THE OXYGENATION PRODUCTS

Mammalian 15-lipoxygenases have been suggested to be involved in cell differentiation and atherogenesis because of their capability of oxyge nating polyenoic fatty acids esterified to biomembranes and lipoprotei ns. We investigated the interaction of the lipid-peroxidizing 15-lipox ygenase and the hydroperoxy lipid-reducing phospholipid hydroperoxide glutathione peroxidase during their reaction with biomembranes and lip oproteins and obtained the following results. 1) Lipoxygenase treatmen t of submitochondrial membranes led to the formation of hydroperoxypho sphatidylethanolamine and hydroperoxyphosphatidylcholine as indicated by high performance liquid chromatography with chemiluminescence detec tion. In 15-lipoxygenase-treated low density lipoprotein cholesteryl h ydroperoxylinoleate was the major oxygenation product. 2) Phospholipid hydroperoxide glutathione peroxidase was capable of reducing the hydr operoxy lipids formed by the 15-lipoxygenase to their corresponding al cohols. 3) Preincubation of low density lipoprotein and submitochondri al membranes with the phospholipid hydroperoxide glutathione peroxidas e completely prevented the lipoxygenase reaction. However, addition of exogenous hydroperoxy lipids restored the oxygenase activity. 4) Shor t-term incubations of the complex substrates with the 15-lipoxygenase led to a specific pattern of oxidation products which was rendered mor e unspecific at long-term incubation or at high substrate concentratio ns. If the phosholipid hydroperoxide glutathione peroxidase was presen t during the reaction, the specific product pattern was preserved. The se data indicate that the phospholipid hydroperoxide glutathione perox idase is capable of reducing hydroperoxy ester lipids formed by a 15-l ipoxygenase, and that it may down-regulate the 15-lipoxygenase pathway s in mammalian cells. The specificity of 15-lipoxygenase-derived hydro peroxy lipids depends on their immediate reduction to the correspondin g alcohols preventing postcatalytic isomerization.