Lipid Oxidation in Human Low-Density Lipoprotein Induced by Metmyoglobin/H2O2: Involvement of α-Tocopheroxyl and Phosphatidylcholine Alkoxyl Radicals

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Abstract
Metmyoglobin (metMb) and H2O2 can oxidize low-density lipoprotein (LDL) in vitro, and oxidized LDL may be atherogenic. The role of α-tocopherol (α-TOH) in LDL oxidation by peroxidases such as metMb is unclear. Herein, we show that during metMb/H2O2-induced oxidation of native LDL, α-tocopheroxyl radical (α-TO•) and hydroperoxides and alcohols of cholesteryl esters [CE-O(O)H] and phosphatidylcholine [PC-O(O)H] accumulate concomitantly with α-TOH consumption. The ratio of accumulating CE-O(O)H to PC-O(O)H remains constant as long as α-TOH is present. Accumulation of CE-O(O)H is dependent on, and correlates with, LDL's α-TOH content, yet does not require preformed lipid hydroperoxides or H2O2. This indicates that in native LDL α-TOH can act as a phase-transfer agent and α-TO• as a chain-transfer agent propagating LDL lipid peroxidation via tocopherol-mediated peroxidation (TMP). After α-TOH depletion, CE-O(O)H continues to accumulate, albeit at a slower rate than in the presence of α-TOH. This second phase of LDL oxidation is accompanied by depletion of PC-OOH, a rapid increase in the CE-O(O)H/PC-O(O)H ratio, formation of lipid-derived alkoxyl radicals and phosphatidylcholine hydroxides (PC-OH), and accumulation of a second organic radical, characterized by a broad singlet EPR signal. The latter persists for several hours at 37 °C. We conclude that metMb/H2O2-induced peroxidation of LDL lipids occurs initially via TMP. After α-TOH depletion, cholesteryl esters peroxidize at higher fractional rates than surface phospholipids, and this appears to be mediated at least in part via reactions involving alkoxyl radicals derived from the peroxidatic activity of metMb on PC-OOH.

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