Many cholesterol-laden foam cells in atherosclerotic lesions are macrophages and much of their cholesterol is present in their lysosomes and derived from low density lipoprotein (LDL). LDL oxidation has been proposed to be involved in the pathogenesis of atherosclerosis. We have shown previously that LDL can be oxidised in the lysosomes of macrophages. a-Tocopherol has been shown to inhibit LDL oxidation in vitro, but did not protect against cardiovascular disease in large clinical trials. We have therefore investigated the effect of a-tocopherol on LDL oxidation at lysosomal pH (about pH 4.5). LDL was enriched with a-tocopherol by incubating human plasma with a-tocopherol followed by LDL isolation by ultracentrifugation. The a-tocopherol content of LDL was increased from 14.4 ± 0.2 to 24.3 ± 0.3 nmol/mg protein. LDL oxidation was assessed by measuring the formation of conjugated dienes at 234 nm and oxidised lipids (cholesteryl linoleate hydroperoxide and 7-ketocholesterol) by HPLC. As expected, LDL enriched with a-tocopherol was oxidised more slowly than control LDL by Cu 2þ at pH 7.4, but was not protected against oxidation by Cu 2þ or Fe 3þ or a low concentration of Fe 2þ at pH 4.5 (it was sometimes oxidised faster by a-tocopherol with Cu 2þ or Fe 3þ at pH 4.5). a-Tocopherol-enriched LDL reduced Cu 2þ and Fe 3þ into the more pro-oxidant Cu þ and Fe 2þ faster than did control LDL at pH 4.5. These findings might help to explain why the large clinical trials of a-tocopherol did not protect against cardiovascular disease.

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