Cholesterol Peroxidation as a Special Type of Lipid Oxidation in Photodynamic Systems

Like other unsaturated lipids in cell membranes and lipoproteins, cholesterol (Ch) is susceptible to oxidative modification, including photodynamic oxidation. There is a sustained interest in the pathogenic properties of Ch oxides such as those generated by photooxidation. Singlet oxygen (1O2)‐mediated Ch photooxidation (Type II mechanism) gives rise to three hydroperoxide (ChOOH) isomers: 5α‐OOH, 6α‐OOH and 6β‐OOH, the 5α‐OOH yield far exceeding that of the others. 5α‐OOH detection is relatively straightforward and serves as a definitive indicator of 1O2 involvement in a reaction, photochemical or otherwise. Like all lipid hydroperoxides (LOOHs), ChOOHs can disrupt membrane or lipoprotein structure/function on their own, but subsequent light‐independent reactions may either intensify or attenuate such effects. Such reactions include (1) one‐electron reduction to redox‐active free radical intermediates, (2) two‐electron reduction to redox‐silent alcohols and (3) translocation to other lipid compartments, where (1) or (2) may take place. In addition to these effects, ChOOHs may act as signaling molecules in reactions that affect cell fates. Although processes a‐c have been well studied for ChOOHs, signaling activity is still poorly understood compared with that of hydrogen peroxide. This review focuses on these various aspects Ch photoperoxidation and its biological consequences. Cholesterol‐5α‐hydroperoxide (5α‐OOH) is the major product of singlet oxygen (1O2)‐mediated photosensitized peroxidation of cholesterol, a monoenoic lipid in cell membranes and lipoproteins. In the presence of redox‐active metal ions and reductants, 5α‐OOH undergoes one‐electron reduction to free radical species that can induce light‐independent chain peroxidation reactions which exacerbate oxidative damage/dysfunction. Seleno‐peroxidase GPx4‐catalyzed two‐electron reduction of 5α‐OOH opposes these effects, yet 5α‐OOH remains one of the most noxious of the known natural lipid hydroperoxides. These and related aspects of photodynamic cholesterol peroxidation are discussed in this review.