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Myeloperoxidase, a heme protein secreted by activated phagocytes, uses hydrogen peroxide to produce potent cytotoxins. One important substrate is chloride, which is converted to hypochlorous acid (HOCl). This diffusible oxidant plays a critical role in the destruction of invading pathogens. Under pathological conditions, HOCl may also injure normal tissue. Recent studies have shown that myeloperoxidase is a component of human atherosclerotic lesions. Because oxidized lipoproteins may play a central role in atherogenesis, we have explored the possibility that cholesterol is a target for damage by myeloperoxidase. Three major classes of sterol oxidation products were apparent when cholesterol-phosphatidylcholine multilamellar vesicles which had been exposed to a myeloperoxidase-hydrogen peroxide-chloride system were subsequently analyzed by normal-phase thin layer chromatography. The products were identified by gas chromatography-mass spectrometry as cholesterol alpha- and beta-chlorohydrins (6 beta-chlorocholestane-3 beta,5 alpha-diol and 5 alpha-chlorocholestane-3 beta,6 beta-diol), cholesterol alpha- and beta-epoxides (cholesterol 5 alpha,6 alpha-epoxide and cholesterol 5 beta,6 beta-epoxide), and a novel cholesterol chlorohydrin. Conversion of cholesterol to the oxidation products required active myeloperoxidase, hydrogen peroxide, and halide and could be blocked by catalase or by scavengers of HOCl. Moreover, in the absence of the enzymatic system, reagent HOCl generated the same distribution of products. These results indicate that myeloperoxidase can convert cholesterol to chlorohydrins and epoxides by a reaction involving HOCl. Other oxygenated sterols are cytotoxic and mutagenic and are potent regulators of cholesterol homeostasis in cultured mammalian cells. Cholesterol chlorohydrins might similarly mediate powerful biological effects in the artery wall. Because chlorohydrins are stable under our experimental conditions, chlorinated sterols may prove useful as markers for lipoproteins oxidatively damaged by activated phagocytes.
Heinecke et al. (Mon,) studied this question.