Radical acetoacetate oxidation by myeloperoxidase, lactoperoxidase, prostaglandin synthetase, and prostacyclin synthetase: implications for atherosclerosis.

When the myeloperoxidase-catalyzed peroxidation of acetoacetate proceeds in the presence of piperidinooxy free radical, methyl glyoxal is formed, and the nitroxide group is reduced to the secondary amine. A mechanism is advanced wherein an alpha-carbon-centered acetoacetate radical, generated by the peroxidase, forms an unstable adduct with the nitroxide group, subsequently decomposing to the observed products. Formation of methyl glyoxal, detected as its bis-2,4-dinitrophenylhydrazone by radial thin-layer chromatography, represents a method of determining free radical acetoacetate peroxidation by other peroxidases. It is shown that lactoperoxidase, prostaglandin synthetase, and prostacyclin synthetase generate methyl glyoxal with requirements identical to those of myeloperoxidase. With prostaglandin synthetase, arachidonic acid could replace the supporting peroxide. Substantiation that the catalyst for the reaction in aortic microsomes was prostacyclin synthetase was obtained by showing that 15-hydroperoxyarachidonic acid strongly inhibited the activity (5). The finding that these peroxidases catalyze radical acetoacetate oxidation could have broad implications for cellular damage via lipid peroxidation (7). Specifically, radical oxidation of acetoacetate by prostacyclin synthetase is proposed to be a link between cardiovascular risk factors and the initiation of atherosclerosis.