Glutathione, function oxidation

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. 

Perhaps this may be considered in relation to the suggestion of Kellermeyer et al. (K5) that the drugs involved are transformed in vivo to redox intermediates. Furthermore, the reducing capacity of RBC was shown to be a function of GSH content. Reduction of this capacity by intravenous infusion of sodium thiosulfate solution reflects changes in the intracellular oxidation-reduction system of glutathione, the oxidized form being favored (Cl, S9). 

Activation of the polyol pathway results in a decrease of NADPH and NAD+ these are necessary cofactors in redox reactions throughout the body. The decreased concentration of these cofactors leads to decreased synthesis of reduced glutathione, nitric oxide, myoinositol and taurine. Myoinositol is particularly required for the normal function of nerves. Sorbitol may also glycate the amino nitrogen on proteins such as collagen, forming AGEs. 

Oxidation alone of pyridine nucleotides is not sufficient to induce Ca release. In the presence of ATP, the hydroperoxide-induced pyridine nucleotide oxidation is even accelerated, yet pyridine nucleotide hydrolysis and Ca release are inhibited [11]. Similar observations were made during the menadione-induced Ca release [10]. When liver mitochondria are treated with N-ethyl maleimide to lower intramitochondrial glutathione, both oxidation of pyridine nucleotides and Ca " release are inhibited (S. Baumhuter, C. Richter, unpubl.). Finally, both pyridine nucleotide hydrolysis and Ca release show the same sigmoidal dependence on the mitochondrial Ca load [15]. Thus, there is clear, albeit circumstantial, evidence that pyridine nucleotide hydrolysis and Ca " release are functionally related. The link between the two processes may be protein ADP-ribosylation. 

The source of the methyl group is S-adenosylmethionine. Glutathione functions as a reducing agent and undergoes reversible oxidative coupling to a disulfide. 

If cellular redox state, determined by the glutathione status of the heart, plays a role in the modulation of ion transporter activity in cardiac tissue, it is important to identify possible mechanisms by which these effects are mediated. Protein S-,thiolation is a process that was originally used to describe the formation of adducts of proteins with low molecular thiols such as glutathione (Miller etal., 1990). In view of the significant alterations of cardiac glutathione status (GSH and GSSG) and ion-transporter activity during oxidant stress, the process of S-thiolation may be responsible for modifications of protein structure and function. 

The most important product of the hexose monophosphate pathway is reduced nicotinamide-adenine dinucleotide phosphate (NADPH). Another important function of this pathway is to provide ribose for nucleic acid synthesis. In the red blood cell, NADPH is a major reducing agent and serves as a cofactor in the reduction of oxidized glutathione, thereby protecting the cell against oxidative attack. In the syndromes associated with dysfunction of the hexose monophosphate pathway and glutathione metabolism and synthesis, oxidative denaturation of hemoglobin is the major contributor to the hemolytic process. 

The presence at the BBB of members of the multidrug resistance-associated protein (MRPs) family, whose members preferentially transport anionic compounds, is still controversial. The seven members of the MRP family belong, like P-gp, to the ATP-binding cassette (ABC) protein superfamily. Mrpl has been found at the BBB in isolated rat brain capillaries, primary cultures of brain capillary endothelial cells and in immortalized capillary endothelial cells, but not in human brain capillaries [59]. Another member, MRP2 has been found at the luminal membrane of the brain endothelial cells [60]. However, further studies are required to show that there are MRP transporters at the BBB (Figure 15.5). As for P-gp, a functional Mrpl was found in primary cultured rat astrocytes [56] and it has been shown to take part in the release of glutathione disulfide from brain astrocytes under oxidative stress [61]. 

Metallothioneins (MT) are unique 7-kDa proteins containing 20 cysteine molecules bounded to seven zinc atoms, which form two clusters with bridging or terminal cysteine thiolates. A main function of MT is to serve as a source for the distribution of zinc in cells, and this function is connected with the MT redox activity, which is responsible for the regulation of binding and release of zinc. It has been shown that the release of zinc is stimulated by MT oxidation in the reaction with glutathione disulfide or other biological disulfides [334]. MT redox properties led to a suggestion that MT may possesses antioxidant activity. The mechanism of MT antioxidant activity is of a special interest in connection with the possible antioxidant effects of zinc. (Zinc can be substituted in MT by some other metals such as copper or cadmium, but Ca MT and Cu MT exhibit manly prooxidant activity.)... 

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