Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems

Abstract

Cholesterol (Ch) is like other unsaturated lipids in being susceptible to peroxidative degradation upon exposure to strong oxidants like hydroxyl radical or peroxynitrite generated under conditions of oxidative stress. In the eukaryotic cell plasma membrane, where most of the cellular Ch resides, peroxidation leads to membrane structural and functional damage from which pathological states may arise. In lipoprotein LDL, Ch and phospholipid peroxidation has long been associated with atherogenesis. Among the many intermediates/products of Ch oxidation, hydroperoxide species (ChOOHs) have a number of different fates and deserve special attention. These fates include (a) damage-enhancement via iron-catalyzed one-electron reduction, (b) damage containment via two-electron reduction, and (c) inter-membrane, inter-lipoprotein, and membrane-lipoprotein translocation, which allows dissemination of one-electron damage or off-site suppression thereof depending on antioxidant location and capacity. In addition, ChOOHs can serve as reliable and conveniently detected mechanistic reporters of free radical- versus non-radical (e.g. singlet oxygen)-mediated reactions. Iron-stimulated peroxidation of Ch and other lipids underlies a newly discovered form of regulated cell death called ferroptosis. These and other deleterious consequences of radical-mediated lipid peroxidation will be discussed in this review.

Ferroptosis: mechanisms and links with diseases

“… 35 This fact suggests that MUFAs are not the substrate of lipid peroxidation during ferroptosis. In addition, sterol lipids, including cholesterols, can be oxidized in membranes or low-density lipoprotein particles, 36 and oxidized cholesterol is also the active substrate of GPx4. 37 However, exogenous cholesterol treatment is not enough to regulate the lethality of RSL3 in human cancer cells.…”

Nitric Oxide‐elicited Resistance to Antitumor Photodynamic Therapy via Inhibition of Membrane Free Radical‐mediated Lipid Peroxidation

“…Like unsaturated phospholipids (PLs), cholesterol (Ch) can be converted to a primary hydroperoxide (ChOOH) by photodynamic action, followed by iron‐catalyzed ChOOH 1‐electron reduction and initiation of highly damaging chain peroxidation reactions (33,34). Ch is found in all membrane compartments of eukaryotic cells, but most of it (>80%) is typically located in the plasma membrane, where it accounts for ~ 45 mol% of total lipid.…”

“…In free radical‐mediated reactions, another positional ChOOH typically predominates, 7α‐OOH and 7β‐OOH, the latter epimer being more stable than the former (36). Several other Ch oxides (ChOX) are generated during propagation reactions; most of these are stable nonperoxide end‐products, for example the diols 7α‐OH and 7β‐OH (33,34). Since Ch is a single molecular species, its photooxidized derivatives can be isolated, identified and quantified more readily than PL counterparts.…”

“…Since Ch is a single molecular species, its photooxidized derivatives can be isolated, identified and quantified more readily than PL counterparts. Consequently, mechanistic information based on detection of 5α‐OOH as a specific 1 O 2 reporter and 7α/β‐OOH as a free radical reporter has been obtained for a variety of model membrane, isolated natural membrane and cellular systems (33,34). Much of this information has been obtained using high‐performance liquid chromatography with mercury cathode electrochemical detection [HPLC‐EC(Hg)], an ultrahigh sensitivity/specificity technique developed in the author’s laboratory (37).…”

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

“…Lipid hydroperoxides (LOOHs) are important intermediates in the nonenzymatic oxidation of all unsaturated lipids, including phospholipids and Ch (4,8,9). In free radical-mediated reactions, including Type I photooxidation reactions, where O 2 levels are relatively low, Ch gives rise to two epimeric ring hydroperoxides (ChOOHs): 3b-hydroxycholest-5-ene-7a-hydroperoxide (7a-OOH) and 3b-hydroxycholest-5-ene-7b-hydroperoxide (7b-OOH) (3,(9)(10)(11) (Fig. 1).…”