Glutathione disulfide metabolites

Glutamylcysteine synthetase, cysteine, or methionine was 100 times more reactive to hypochlorous acid in comparison with amino acids that did not contain thiol groups (Folkes et al., 1995). Sublethal exposures to HOCl decreased GSH levels in several cell types (Vissers and Winterboum, 1995 Pullar et al., 1999). In a study by Pullar et al. (1999) using human umbilical vein endothelial cells, doses of 25 nmol of HOCl and less were sublethal when the exposure was done over 10 min, there was a concentration-dependent loss of intracellular GSH. Tissue exposure to HOCl resulted in a reduction of GSH. The metabolite of the HOCl interaction with GSH was an unexpected cyclic sulfonamide that was exported from the cell. The expected metabolites of glutathione disulfide (GSSH) and GSH sulfonic acid were actually minimal (Pullar et al., 2001). Inactivation of acetylcholinesterase by HOCl could be a contributory cause of airway hyperreactivity (den Hartog et al., 2002). 

The kidneys are the primary route of excretion of carbon disulfide metabolites. Conjugation of carbon disulfide or carbonyl sulfide with endogenous glutathione results in formation of thiozolidine-2-thione-4-carboxylic acid and 2-oxythiazolidine-4-carboxylic acid, respectively, which are excreted in the urine. 

Measuring the total concentration of urinary thio compounds (including glutathione conjugates, mercapturic acids, and other sulfur-containing carbon disulfide metabolites) can serve as a good marker of exposure. The level of total thio compounds correlates with carbon disulfide exposure levels and is a more sensitive biomarker of exposure than the iodine-azide test (Beauchamp et al. 1983 Van Doom et al. 

A.J.J. Debets, R. Van De Straat, W.H. Voogt, H. Vos, N.P.E. Vermeulen and R.W. Frei, Simultaneous determination of glutathione, glutathione disulfide, paracetamol and its sulfur containing metabolites by HPLC with electrochemical detection with on-line generated bromine, J. Pharm. Biomed. Anal., 1988, 6, 329-336. 

As already discussed in chapter 4, reactive intermediates can react with reduced GSH either by a direct chemical reaction or by a GSH transferase-mediated reaction. If excessive, these reactions can deplete the cellular GSH. Also, reactive metabolites can oxidize GSH and other thiol groups such as those in proteins and thereby cause a change in thiol status. When the rate of oxidation of GSH exceeds the capacity of GSH reductase, then oxidized glutathione (GSSG) is actively transported out of the cell and thereby lost. Thus, reduced GSH may be removed reversibly by oxidation or formation of mixed disulfides with proteins and irreversibly by conjugation or loss of the oxidized form from the cell. Thus, after exposure of cells to quinones such as menadione, which cause oxidative stress, GSH conjugates, mixed disulfides, and GSSG are formed, all of which will reduce the cellular GSH level. 

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