Oxidation of low density lipoprotein (LDL) may trigger pathological events in atherosclerosis. Myeloperoxidase (MPO), a heme protein secreted by phagocytes, is a potent catalyst for LDL oxidation in vitro, and active enzyme is present in human atherosclerotic lesions. Reactive intermediates generated by MPO may target LDL cholesterol for oxidation. LDL exposed to the MPO-H2O2-C1 system at acidic pH yielded a family of chlorinated sterols. The products were identified by mass spectrometry as cholesterol (-chlorohydrin (6(-chlorocholestane-(3(,5()-diol), cholesterol (-chlorohydrin (5(-chlorocholestane-(3(,6()-diol), a structurally related cholesterol chlorohydrin, and a novel dichlorinated sterol. Oxidation of LDL cholesterol by myeloperoxidase required H2O2 and C1, suggesting that hypochlorous acid (HOC1) is an intermediate in the reaction. HOC1 failed to generate chlorinated sterols under chloride-free conditions. Since HOC1 is in equilibrium with molecular chlorine th rough a reaction which requires C1 and H+, C12 may be the chlorinating intermediate. Consonant with this hypothesis, HOC1 oxidized LDL cholesterol in the presence of Cl- at acidic pH. In the absence of Cl- at neutral pH, C12 generated the same family of chlorinated sterols as the MPO-H2O2-C1 system. Direct addition of C12 to the double bond of cholesterol accounts for dichlorinated sterol formation by MPO. These results indicate that C12 derived from HOC1 is the chlorinating intermediate in the oxidation of cholesterol by MPO.
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