Surprising Inability of Singlet Oxygen‐generated 6‐Hydroperoxycholesterol to Induce Damaging Free Radical Lipid Peroxidation in Cell Membranes†

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Abstract
Singlet oxygen attack on cholesterol (Ch), a prominent monounsaturated lipid of mammalian cell plasma membranes, gives rise to three hydroperoxide (ChOOH) isomers, 5α‐OOH, 6α‐OOH and 6β‐OOH, the latter two in lower yield than 5α‐OOH, and 6α‐OOH in lowest yield. A third possible positional isomer, 7α‐OOH and 7β‐OOH, is produced by free radical attack. In the presence of iron and ascorbate (Fe/AH), 5α‐OOH or 6β‐OOH in phosphatidylcholine/Ch/ChOOH (20:15:1 by mol) liposomes was reduced to its corresponding alcohol, the rate constant being approximately the same for both ChOOHs. Using [14C]Ch as an in situ probe, we found that liposomal 5α‐OOH readily set off free radical‐mediated (chain) peroxidation reactions when exposed to Fe/AH, whereas 6β‐OOH under the same conditions did not. Moreover, liposomal 5α‐OOH triggered robust chain peroxidation in [14C]Ch‐labeled L1210 cells, leading to cell death, whereas 6β‐OOH was essentially inert in this regard. Thus, 5α‐OOH and 6β‐OOH undergo iron‐catalyzed reductive turnover, but only the former can provoke toxic membrane damage. These novel findings have important implications for UVA‐induced photodamage in Ch‐rich tissues like skin and eye, where 1O2 often plays a major role.

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