Oxidised glutathione

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)...

Darley-Usmar, V.M., Severn, A., O Leary, V.J. and Ro rs, M. (1991). Treatment of macrophages with oxidised low density liproprotein increases their intracellular glutathione content. Biochem. J. 278, 429-434. 

Gotoh, N., Graham, A., Niki, E. anel Darley-Usmar, V.M. (1993). Inhibition of glutathione synthesis increases the toxicity of oxidised LDL to human monoctites and macrophages. Biochem. J. 296, 151-154. 

Haddock, P.S., Woodward, B., Hearse, D.J. and Dodds, R. (1991). Modification of the activity of bovine Na/K ATPase by reduced and oxidised glutathione and other sulphydryl compounds. Br. J. Pharmacol. 102, 54P. 

Other non-metals became oxidised, such as selenium to selenate, and this element became a detoxifying agent, used in destroying peroxides, e.g. in glutathione peroxidase, as well as a hydrogen transfer centre. 

Microtubules may function as a form of skeletal support for microfilaments. Agents that increase intracellular cGMP favour the assembly of microtubules, whereas those that increase intracellular Ca2+ and cAMP result in the dissolution of tubulin fibres. Furthermore, the oxidation state of the neutrophil may affect the integrity of the tubulin fibres. Oxidised glutathione (which is increased during oxidative metabolism) regulates tubulin disassembly, and oxidation may increase tubulin tyrosylation, which also promotes disassembly. 

Figure 5.3. The glutathione cycle. Abbreviations HMP, hexose monophosphate shunt GSH, reduced glutathione GSSH, oxidised glutathione GR, glutathione reductase GPO, glutathione peroxidase. In the system shown, H2O2 is converted into H20, but the system is also effective in breaking down organic peroxides.

GSSG = oxidised glutathione GSH = reduced glutathione RX = toxic compound... 

Since this reaction is required continuously, the oxidised glutathione must be reduced continuously and this is achieved with NADPH, as follows... 

Fig. 11. XPS spectra of glutathione peroxidase. The arrows are indicative for Se 3d(3Q ) lying between Na2s at 62.2 eV and Mg 2 p at 50.8 eV. (a) The native enzyme, (b) after the addition of H2O2, (c) reduction of the H2O2 oxidised enzyme with glutatione (with permission of Biochim. Biophys. Acta 277, 213 (1975))...

Ions of several metals such as zinc, cadmium, lead, nickel, and mercury form very stable complexes with glutathione, disturb the interconversion of oxidised reduced glutathione, which results in a lowering of the level of available antioxidants in cells (Christie and Costa, 1984). 

Hahn, B., Grosch, W. 1998. Distribution of glutathione in Osborne fractions as affected by additions of ascorbic acid, reduces and oxidised glutathione. J Cereal Sci 27 117-125. 

Koehler, P. 2003. Effect of acid in dough Reduction of oxidised glutathione with reactive thiol groups of wheat glutelin. J Agric Food Chem 51 4954-4959. 

Fig. 11. Sketch of one active site of the dimeric enzyme glutathione reductase, from the work of Schulz and colleagues [53]. Oxidised glutathione binds between subunits. Hydrogen is transferred via the FAD.

Other methods of bioactivation have been suggested. Using a pig liver enzyme Heppel and Hilmoe [54] observed that GTN reacted with reduced glutathione to form oxidised glutathione and inorganic nitrite. This led to the suggestion by Needleman and Hunter [55] that the major route for GTN transformation appeared to be denitration in the presence or reduced glutathione. 

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