Metmyoglobin (metMb) and H(2)O(2) can oxidize low-density lipoprotein (LDL) in vitro, and oxidized LDL may be atherogenic. The role of alpha-tocopherol (alpha-TOH) in LDL oxidation by peroxidases such as metMb is unclear. Herein, we show that during metMb/H(2)O(2)-induced oxidation of native LDL, alpha-tocopheroxyl radical (alpha-TO(*)) and hydroperoxides and alcohols of cholesteryl esters [CE-O(O)H] and phosphatidylcholine [PC-O(O)H] accumulate concomitantly with alpha-TOH consumption. The ratio of accumulating CE-O(O)H to PC-O(O)H remains constant as long as alpha-TOH is present. Accumulation of CE-O(O)H is dependent on, and correlates with, LDL's alpha-TOH content, yet does not require preformed lipid hydroperoxides or H(2)O(2). This indicates that in native LDL alpha-TOH can act as a phase-transfer agent and alpha-TO(*) as a chain-transfer agent propagating LDL lipid peroxidation via tocopherol-mediated peroxidation (TMP). After alpha-TOH depletion, CE-O(O)H continues to accumulate, albeit at a slower rate than in the presence of alpha-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 degrees C. We conclude that metMb/H(2)O(2)-induced peroxidation of LDL lipids occurs initially via TMP. After alpha-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.