title: Surprising inability of singlet oxygen-generated 6-hydroperoxycholesterol to induce damaging free radical lipid peroxidation in cell membranes.
abstract: Singlet oxygen attack on cholesterol (Ch), a prominent monounsaturated lipid of mammalian cell plasma membranes, gives rise to three hydroperoxide (ChOOH) isomers, 5alpha-OOH, 6alpha-OOH and 6beta-OOH, the latter two in lower yield than 5alpha-OOH, and 6alpha-OOH in lowest yield. A third possible positional isomer, 7alpha-OOH and 7beta-OOH, is produced by free radical attack. In the presence of iron and ascorbate (Fe/AH), 5alpha-OOH or 6beta-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 [(14)C]Ch as an in situ probe, we found that liposomal 5alpha-OOH readily set off free radical-mediated (chain) peroxidation reactions when exposed to Fe/AH, whereas 6beta-OOH under the same conditions did not. Moreover, liposomal 5alpha-OOH triggered robust chain peroxidation in [(14)C]Ch-labeled L1210 cells, leading to cell death, whereas 6beta-OOH was essentially inert in this regard. Thus, 5alpha-OOH and 6beta-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 (1)O(2) often plays a major role.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Witold
authors.initials: W
authors.lastname: Korytowski
authors.forename: Jared C
authors.initials: JC
authors.lastname: Schmitt
authors.forename: Albert W
authors.initials: AW
authors.lastname: Girotti
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism / Q000528:radiation effects; D002784:Cholesterol / Q000031:analogs & derivatives / Q000737:chemistry; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D010545:Peroxides / Q000737:chemistry; D010777:Photochemistry; D026082:Singlet Oxygen / Q000737:chemistry* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D005609:Free Radicals; D008081:Liposomes; D010545:Peroxides; D026082:Singlet Oxygen; D002784:Cholesterol
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