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Free Radical Damage and Lipid Peroxidation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Richard O. Recknagel, Eric A. Glende, Robert S. Britton
As is well-known, the polyenoic fatty acids (18:3, 20:4, 22:6) most susceptible to peroxidation are predominantly bound by ester linkage to the number 2 carbon of the glycerol moiety of phospholipids. Lipid hydroperoxides in this position, in addition to their reduction to alcohols by the phospholipid hydroperoxide glutathione peroxidase, can be eliminated through combined action of phospholipase A2 and soluble GSH-dependent peroxidases. Phospholipase A2 cleaves phospholipid ester bonds in the number 2 position. Normally the enzyme is relatively inactive. Through mechanisms that are not fully known, when the normal configurational structure of a membrane is altered as a result of insertion of oxygen functions, as in lipoperoxidation, the affected membrane site becomes accessible to phospholipase A2, and this enzyme preferentially hydrolyzes peroxidized fatty acid esters in phospholipid membranes relative to rates of hydrolysis of nonperoxidized fatty acid esters (Sevanian and Kim, 1985). The hepatocellular cytoplasm contains a selenium-dependent glutathione peroxidase which reduces free fatty acid hydroperoxides to the corresponding fatty acid alcohol. The active site of the enzyme is reduced selenium (see Simic, 1981, for literature citations) which reduces the lipid hydroperoxide to the lipid alcohol:
Role of Astrocytes in Maintaining Cerebral Glutathione Homeostasis and in Protecting the Brain Against Xenobiotics and Oxidative Stress
Published in Christopher A. Shaw, Glutathione in the Nervous System, 2018
Hydrogen peroxide and other peroxides, including lipid peroxides, are reduced by the selenium-containing enzyme glutathione peroxidase [Eq. (2)], which is present in most tissues. In addition, many tissues, including brain, contain a distinct phospholipid hydroperoxide glutathione peroxidase. The two peroxidases function in the protection of cell membranes against oxidative damage. Reduction of lipid peroxides is also catalyzed by certain glutathione S-transferases and by a low molecular weight form of glutathione peroxidase. Lipids are protected against free radical damage in part by α-tocopherol (vitamin E), which quenches free-radical propagation by formation of the oxy radical form of α-tocopherol. This free radical does not propagate but is reduced by GSH in an apparent nonenzymatic reaction (Fig. 1, reaction 10). This reaction and those catalyzed by glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, and the transhydrogenases lead to the formation of GSSG, which does not normally accumulate because it is rapidly reduced by GSSG reductase [Eq. (1)]:
Problems on Deficiency and Excess of Minerals In Animal Nutrition
Published in Jul Låg, Geomedicine, 2017
It has also been shown that selenium influences the metabolism of arachadonic acid and the formation of prostaglandines.87 Selenium thus seems to be of significance in inflammatory reactions. In addition, it influences the microbicidal activity of polymorphonuclear leukocytes87 as well as the response of lymphocytes to mitogens,88 and thereby probably also the immune response in animals to infectious challenges.89 These modes of action do not yet seem to have been sufficiently elucidated. A second selenium-dependent peroxidase, phospholipid hydroperoxide glutathione peroxidase, has recently been discovered in mammals. This peroxidase is active on membrane-bound hydroperoxides.90
Physiological and pathophysiological roles of hepoxilins and their analogs
Published in Drug Metabolism Reviews, 2023
Sara A. Helal, Fadumo Ahmed Isse, Samar H. Gerges, Ayman O. S. El-Kadi
HxA3 metabolism is mediated by the enzymes cytoplasmic glutathione peroxidase (cGPx) and phospholipid hydroperoxide glutathione peroxidase (PHGPx). Both overexpression and deficiency of cGPx and PHGPx cause decreased synthesis of HxA3 and increased synthesis of HxA3, respectively (Zafiriou et al. 2007). Overexpression of the 12/15-LOX enzyme did not result in the formation of HxA3 or 12S-HETE in the presence of high cGPx and PHGPx levels in the cells (Pattabhiraman 2003). Native HXs are unstable due to their propensity to be hydrolyzed to trioxilins (TrX) by hepoxilin epoxide hydrolase or by glutathione S-transferase to form a glutathione conjugate, hepoxilin A3-C (Figure 2) (Pace-Asciak et al. 1983, 1989; El-Sherbeni and El-Kadi 2014b). Thus, researchers in 1993 developed four stable cyclopropyl analogues of HX named proprietary bioactive therapeutic (PBTs) (Demin and Pace-Asciak 1993) with a structure of 10-hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z trienoic acid to study the role of native HXs in vivo (Pace-Asciak 2009). HXs levels differ between in vivo and in vitro models; in vitro, HXs are high due to GPx scarcity (Wang MM et al. 1999), whereas they are lower in vivo due to the abundance of hydrolyzes (Laneuville et al. 1991).
Chondrocyte protein co-synthesis network analysis links ECM mechanosensing to metabolic adaptation in osteoarthritis
Published in Expert Review of Proteomics, 2021
Aspasia Destouni, Konstantinos C. Tsolis, Anastassios Economou, Ioanna Papathanasiou, Charalampos Balis, Evanthia Mourmoura, Aspasia Tsezou
Integration of phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) connected the proteins involved in glutathione metabolism (glutathione S-transferase Mu 2 [GSTM2], glutathione S-transferase Mu 3 [GSTM3] and glutathione synthetase [GSS]) to the core interactome, which remained unconnected in the healthy network (Figure 4a, Figure 5a). GPX4 is a key enzyme that reduces phospholipid hyperoxides to alcohols and protects cells from ferroptosis [50], a process of cell death. A cell density-induced adaptive mechanism rescues cells from the lipotoxic conditions by sequestering poly-unsaturated fatty acid (PUFA) TGAs in lipid droplets (LDs) protecting cells from ferroptosis [51]. Lysophosphatidylcholine acyltransferase 1 (LPCAT1), one of the Lands cycle key enzymes, responsible for phospholipid remodeling at membranes, was exclusive to the OA interactome. LPCAT1 has been found to localize to the phosphatidylcholine (PC) monolayer membrane of the neutral triacylglycerol (TGA) containing lipid droplet (LD) [52].
Ameliorative effect of selenium nanoparticles and fish oil on cisplatin and gamma irradiation-induced nephrotoxicity in male albino rats
Published in Drug and Chemical Toxicology, 2019
Mostafa Saif-Elnasr, Nahed Abdel-Aziz, Ahmed Ibrahim El-Batal
Selenium is essential micronutrient which plays a fundamental role in humans and animals and has been implicated to have important health benefits. In humans, Se has one of the narrowest ranges between dietary deficiency (<40 mg/day) and toxic levels (>400 mg/day). The dietary reference value of Se intake has been set in the range of 30–55 mg/day by international agencies (Winkel et al.2012). Se, in the form of selenocysteine, functions as a redox center of an array of selenoproteins (Copeland 2003, Driscoll and Copeland 2003), some of which have important enzymatic functions for homoeostasis, such as glutathione peroxidase (De Haan et al.2003, Miyamoto et al.2003), phospholipid hydroperoxide glutathione peroxidase (Nakagawa and Imai 2000, Imai and Nakagawa 2003) and thioredoxin reductase (Arner and Holmgren 2000, Becker et al.2000). Studies have shown that selenium nanoparticles (SeNPs) have an efficacy comparable with that of Se compounds as an antioxidant, but have a greatly reduced risk of toxicity (Peng et al.2007, Wang et al.2007).