Glutathione radical

Rauk A, Armstrong DA, Berges J (2001) Glutathione radical intramolecular H abstraction by thiyl radical. Can J Chem 79 405-417... 

This reaction results in production of a glutathione radical, which is relatively stable and unreactive. GSH can also react with superoxide, and here the puniucts are the glutathione radical plus HOOH (Wefers and Sies, 19S3) ... 

Two glutathione radicals can condense with each other to form GSSG ... 

The original radical is destroyed and replaced by a glutathione radical. Two glutathione radicals, formed in this way, can then couple with each other to produce a compound called glutathione disulfide, abbreviated GSSG, which is then ultimately converted back into glutathione ... 

The key to hexavalent chromium s mutagenicity and possible carcinogenicity is the abiHty of this oxidation state to penetrate the cell membrane. The Cr(VI) Species promotes DNA strand breaks and initiates DNA—DNA and DNA-protein cross-links both in cell cultures and in vivo (105,112,128—130). The mechanism of this genotoxic interaction may be the intercellular reduction of Cr(VI) in close proximity to the nuclear membrane. When in vitro reductions of hexavalent chromium are performed by glutathione, the formation of Cr(V) and glutathione thiyl radicals are observed, and these are beHeved to be responsible for the formation of the DNA cross-links (112). 

Figure 45-6. Interaction and synergism between antioxidant systems operating in the lipid phase (membranes) of the cell and the aqueous phase (cytosol). (R-,free radical PUFA-00-, peroxyl free radical of polyunsaturated fatty acid in membrane phospholipid PUFA-OOH, hydroperoxy polyunsaturated fatty acid in membrane phospholipid released as hydroperoxy free fatty acid into cytosol by the action of phospholipase Aj PUFA-OH, hydroxy polyunsaturated fatty acid TocOH, vitamin E (a-tocopherol) TocO, free radical of a-tocopherol Se, selenium GSH, reduced glutathione GS-SG, oxidized glutathione, which is returned to the reduced state after reaction with NADPH catalyzed by glutathione reductase PUFA-H, polyunsaturated fatty acid.)...

Figure 15.11 Possible scheme for the formation of free radicals from the metabolism of dopamine. Normally hydrogen peroxide formed from the deamination of DA is detoxified to H2O along with the production of oxidised glutathione (GSSG) from its reduced form (GSH), by glutathione peroxidase. This reaction is restricted in the brain, however, because of low levels of the peroxidase. By contrast the formation of the reactive OH-radical (toxification) is enhanced in the substantia nigra because of its high levels of active iron and the low concentration of transferin to bind it. This potential toxic process could be enhanced by extra DA formed from levodopa in the therapy of PD (see Olanow 1993 and Olanow et al. 1998)...

In the previous section, we have described some of the mechanisms that may lead to the fijrmation of lipid hydroperoxides or peroxyl radicals in lipids. If the peroxyl radical is formed, then this will lead to propagation if no chain-breaking antioxidants are present (Scheme 2.1). However, in many biological situations chain-breaking antioxidants are present, for example, in LDL, and these will terminate the peroxyl radical and are consumed in the process. This will concomitandy increase the size of the peroxide pool in the membrane or lipoprotein. Such peroxides may be metabolized by the glutathione peroxidases in a cellular environment but are probably more stable in the plasma comjxutment. In the next section, the promotion of lipid peroxidation if the lipid peroxides encounter a transition metal will be considered. 

Figure 4.3 Effect of a variety of anti-free-radical interventions on reperfuslon-induced ventricular fibrillation In the Isolated perfused rat heart. Regional Ischaemia was induced by occluding a snare around the left anterior descending coronary artery and, after 10 min, hearts were reperfused by releasing the snare. Superoxide dismutase (SOD) (1 x 10° U/l), catalase (CAT) (1 X 10 U/l), mannitol (Mann) (50 mM), l-methlonlne (Methlon) (10 mM), glutathione (Glutath) (10 iiM) or desferrioxamlne (Deafer) (150 iim) were included throughout the experimental time course (n = 15/group). Redrawn with permission from Bernier et af. (1986).

Preliminary data, in which extracellular and intracellular glutathione status were altered in the absence of a ffee-radical-induced oxidant stress have demonstrated a similar effect on /Na/K- In these experiments the extracellular concentration of GSH was altered by varying the levels in the extracellular perfusate. In contrast, the intracellular GSH content was controlled by the inclusion of the required concentration of GSH in the patch pipette. After 5 min exposure to GSH there was an approximately 20% increase in /na/K at 0 mV. Conversely, in a separate group of cells, 5 min after the application of GSSG there was an approximately 15% decrease in /wa/K (Haddock, 1991). 

Figure 4.14 Diagrammatic representation of (a) oxy-radical>mediated S-thioiation and (b) thiol/disulphide-initiated S-thiolation of protein suiphydryl groups. Under both circumstances mixed disuiphides are formed between glutathione and protein thiois iocated on the ion-translocator protein resulting in an alteration of protein structure and function. Both of these mechanisms are completely reversible by the addition of a suitabie reducing agent, such as reduced glutathione, returning the protein to its native form.

The free-radical defence mechanisms utilized by the brain are similar to those found in other tissues. The enzymes SOD, catalase, glutathione peroxidase, and the typical radical scavengers, ascorbate, vitamin E and vitamin A are present in the brain, as they are in peripheral tissues. However, the brain may actually be slightly deficient in some of these defence mechanisms when compared to the amounts present in other tissues. 

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