Oxidative glutathione peroxidases

Glutathione peroxidase [9013-66-5] oxidizes glutathione, and helps to remove inorganic and organic hydroperoxides (221] It exhibits antiinflammatory activity in experimental uveitis of rats (234). 

Figure 20-3. Role of the pentose phosphate pathway in the glutathione peroxidase reaction of erythrocytes. (G-S-S-G, oxidized glutathione G-SH, reduced glutathione Se, selenium cofactor.)...

The red cell contains a battery of cytosolic enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, to dispose of powerful oxidants generated during its metabolism. 

Thiols are also important protection against lipid peroxidation. Glutathione (7-Glu-Cys-Gly) is used by several glutathione-dependent enzymes such as free-radical reductase (converts vitamin E radical to vitamin E), glutathione peroxidase (reduces hydrogen peroxide and lipid hydroperoxides to water and to the lipid alcohol, respectively), and others. In addition, the thiol group of many proteins is essential for function. Oxidation of the thiol of calcium ATPases impairs function and leads to increased intracellular calcium. Thiol derivatives such as the ovothiols (l-methyl-4-mercaptohistidines) (Shapiro, 1991) have been explored as therapeutics. 

GSHPx Glutathione peroxidase GSSG Glutathione (oxidized)... 

The importance of having adequate supplies of NADPH for the regeneration of these various enzymes cannot be over emphasized. In normal situations this cofactor can be adequately provided by the reductive pentose phosphate pathway. Monitoring the activity of the pentose phosphate pathway has been proposed as a unique way to study the metabolic response to oxidative stress, since the glutathione peroxidase activity is coupled via glutathione reductase to the enzyme glucose-6-phosphate dehydrogenase (Ben Yoseph et ah, 1994). 

Hernandez-Montes E, Pollard SE, Vauzour D, Jofre-Montseny L, Rota C, Rimbach G, Weinberg PD and Spencer JPE. 2006. Activation of glutathione peroxidase via Nrfl mediates genistein s protection against oxidative endothelial cell injury. Biochem Biophys Res Commun 346(3) 851—859. 

However, subsequent studies demonstrated that the formation of hydroxyl radicals, even if it takes place during lipid peroxidation, is of no real importance. Beloqui and Cederbaum [11] have found that although the glutathione-glutathione peroxidase system suppressed hydroxyl radical generation during the oxidation of 4-methylmercapto-2-oxo-butyrate, it exhibited a much smaller effect on microsomal lipid peroxidation. Therefore, hydroxyl radical formation is apparently unimportant in this process. Other authors also pointed out at an unimportant role of hydroxyl radicals in the initiation of microsomal lipid peroxidation [12 14], For example, it has been shown that Fe(EDTA), a most efficient catalyst of hydroxyl radical formation by the Fenton reaction, inhibited microsomal and liposomal lipid peroxidation, while the weak catalysts of this reaction Fe(ADP) and Fe(ATP) enhanced it [13]. 

O Donnell et al. [70] found that LOX and not cyclooxygenase, cytochrome P-450, NO synthase, NADPH oxidase, xanthine oxidase, ribonucleotide reductase, or mitochondrial respiratory chain is responsible for TNF-a-mediated apoptosis of murine fibrosarcoma cells. 15-LOX activity was found to increase sharply in heart, lung, and vascular tissues of rabbits by hypercholesterolemia [71], Schnurr et al. [72] demonstrated that there is an inverse regulation of 12/15-LOXs and phospholipid hydroperoxide glutathione peroxidases in cells, which balanced the intracellular concentration of oxidized lipids. 

Glutathione peroxidase is a selenium-dependent enzyme, which rapidly detoxifies hydrogen peroxide and various hydroperoxides. Suttorp et al. [67] showed that the impairment of glutathione cycle resulted in an increase in the injury of pulmonary artery endothelial cells. Glutathione cycle protected against endothelial cell injury induced by 15-HPETE, an arachi-donate metabolite produced by 15-lipoxygenase-catalyzed oxidation [68]. 

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