Thiol status

A sustained inhibition of the Na/K pump following a period of oxidant stress would be expected to raise intracellular sodium and favour calcium influx via the Na/Ca exchanger. Ischaemia and reperflision-induced oxidant stress, therefore, may result in a loss of Na/K pump activity, an eflFect that may involve free-radical-mediated changes in cellular thiol status. 

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. 

The cellular injury, which underlies target organ toxicity, may result from various underlying events primary, secondary, and tertiary events. Primary events result from initial damage, for example, lipid peroxidation, enzyme inhibition, covalent binding to crucial macromolecules, ischemia, and changes in thiol status. 

The important primary events that underlie cellular injury are lipid peroxidation, covalent binding, changes in thiol status, enzyme inhibition, and ischemia. 

Mitochondrial membrane permeability transition and its role in the mechanism of toxicity of many chemicals is a major area of research focus. The protein thiol status of mitochondria is crucial to the control of the inner-membrane potential for ATP synthesis and the membrane permeability transition as well as cellular integrity. Protein thiols appear to have a major role in signal transduction and are important in the responses to chemical exposure. 

In addition to GSH, a new line of research is devoted to the evaluation of the total intracellular thiol status. The defective thiols status of the peritoneal macrophages in peritoneal dialysis patients [47] and of the alveolar macrophages in COPD patients and smokers [48] has recently been reported. 

M. Tager, J. Dietmann, U. Thiel, K. Neumann and S. Ansorge, Restoration of the Cellular Thiol Status of Peritoneal Macrophages from CAPD Patients by the Flavonoids Silibinin and Silymarin, Free Rad Res 54 im ) 137-151. 

M. Tager, A. Piecyk, T. Kohnlein, U. Thiel, S. Ansorge and T. Welte, Evidence of a Defective Thiol Status of Alveolar Macrophages from COPD Patients and Smokers, Free Rad Biol Med 29 (2000) 1160-1165. 

Fig. 4. Mechanisms of trace metal-induced porphyria and cell injury i, metals promote increased reactive oxidant formation 2, metals complex with GSH, compromising antioxidant and thiol status 3, metals impair SH-dependent enzymes and other proteins via mercaptide bond formation and/or exchange reactions 4, metal-induced oxidant stress causes oxidation of reduced porphyrins (porphyrinuria) and other biomolecules (cell injury)...

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