GSH synthesis

Among the strategies used for the development of GST Pl-1 inhibitors is the modification of the GSH backbone to leverage its inherent affinity for GST Pl-1. One approach centered on the incorporation of a carbamate group as an isosteric replacement of the y-carboxylic Glu linkage in GSH. Synthesis and in vitro testing of 42 and 43 showed that this carbamate-replacement approach was not well tolerated [67]. 

GSH synthesis. GLUT1 transports dehydroascorbic acid, an oxidized form of vitamin C, to supply the retina with ascorbic acid [47],... 

We have further investigated the dependency of HC "NO synthesis on cellular GSH levels and BH4 availability. Inhibition of GSH synthesis using the 7-glutamylcysteine synthetase inhibitor buthionine sulfoximine, which blocks de novo GSH synthesis, markedly reduced GSH levels in cultured HC, approximately 5% of control, but resulted in only a 40-50% reduction in NO2 biosynthesis in response to cytokines and LPS. More effective was the inhibition of GSH reductase with l,3-bis(chloroethyl)-l-nitrosurea, which prevents the recycling of GSSH back to GSH. GSH levels also fell in these cells, but a marked decrease in NO2" formation was seen, suggesting that GSH recycling was an important aspect of -NO formation. Similar results had been reported for con-... 

Instead of reducing the cellular GSH level, it may also enhanced upon the addition of the drug OTZ which stimulates GSH synthesis thereby approximately doubling the cellular GSH content. At low 02 concentrations, this leads to an increased protection (Russo et al. 1985). 

GSH is not transported into cells. For circulating GSH to increase intracellular GSH concentrations, it must first be hydrolyzed to Glu and CysGly, which are subsequently transported into the cell and serve as substrates for GSH synthesis. Thus, GSH administered orally or parenterally, and that produced by the liver and released into the circulation enhance tissue levels of GSH by providing a source of its constituent amino acids. In contrast, GSH monoesters, which are well absorbed after oral administration, as is GSH, are readily transported to cells and then hydrolyzed to GSH and the corresponding alcohol. Thus, higher cellular levels of GSH result from oral administration of GSH monoesters than from oral administration of comparable doses of GSH. 

Glucose 6-P-dehydrogenase deficiency results in a decrease in NADPH and GSH synthesis, making the cell more sensitive to oxidative agents, such as primaquine. This causes hemolysis. 

In conclusion, these genetic and functional results support the concept that a dysregulation of GSH metabolism, and in particular GSH synthesis, is one of the vulnerability factors that could contribute to the development of schizophrenia. These markers may contribute to obtain a complete picture of genetic risk factors of schizophrenia and may help to identify critical period and specific brain locations during development, where GSH deficits are important to the emergence of the disease. 

Within the liver there will be competition between acute phase protein and GSH synthesis for the cellular sulphur amino acid pool. The question therefore arises whether incorporation of Cysteine into both of these end-products, during the inflammatory response, is influenced equally by alteration in dietary sulphur amino acid intake... An insufficient intake of sulphur amino acids will thereby exert a pro-inflammatory influence... 

In addition, in rats a non-lethal dose of TNF-a becomes lethal if the ability of the animal to increase and maintain GSH synthesis is prevented by administration of diethyl-maleate [36]. 

GSH is synthesized from its constituent amino acids by the sequential action of gamma-glutamylcysteine synthetase (y-GCS) and GSH synthetase. The rate-limiting enzyme in GSH synthesis is y-GCS. Interestingly y-GCS expression is also modulated by intracellular redox state in a delicate balance among oxidants, antioxidants, inflammatory and anti-inflammatory agents [22]. 

In a study of six mercury compounds, mercury chloride, mercury nitrate, sodium ethylmercurithi-osalicylate, methyl mercury chloride, mercury acetate and phenylmercury acetate in MDCK cells, LLC-PKl cells and human primary proximal tubular cells (hPTC) and non-renal cell lines (SAOS and Hep G2) it was found that all mercury compounds were toxic to all cell types as evidenced by neutral red uptake, thymidine incorporation and the MTT assay [189]. However, sodium ethylmercurithiosalicylate, methyl mercury chloride and phenylmercury acetate were one order of magnitude more toxic than the other compounds. In addition the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) potentiated the toxicity of all mercury compounds [189]. In a study using primary rabbit proximal tubular cells it was also shown that methyl mercury chloride is more toxic than mercury chloride [190]. Differences in the extent and rate of metal uptake were also evident. Maximum cellular uptake of Hg " occurred within 6-24 hr after exposure and was not concentration-dependent, whereas maximum uptake of CHgHg" occurred within 3 hr of exposure and was concentration- dependent [190]. 

A second application of PBPD modeling was the analysis of the toxicodynamic interactions between trichloroethylene (TCE) and 1,1-dichloroethylene (DCE) [97], The interactions examined were related to the binding of these chemicals to, and depletion of, hepatic glutathione (GSH) in relation to the intrinsic hepatic GSH synthesis, a protective mechanism toward DCE toxicity. PBPK models for interactions leading to depletion of hepatic glutathione had... 

Erythrocyte GSH concentration is diminished in many people who have defects in the hexose monophosphate or GSH synthesis pathways. The GSH stability test, originally devised to permit identification of people susceptible to hemolysis from primaquine (later shown to be the result of G6PD deficiency), still remains a useful "stress test of the intactness of these closely hnked pathways. Because deficiencies of GSH synthetase and y-glutamyl cysteine synthetase are rare disorders, it is not practical for clinical laboratories to contemplate assays for these enzymes unless results of the easily performed GSH stability test are abnormal. 

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