Thiol depletion

Moore, M., Thor, H., Moore, G., Nelson, S., Moldeus, P. and Orrenius, S. (1985). The toxicity of acetaminophen and N-acetyl-/>-benzoquinone imine in isolated hcpatocytes is associated with thiol depletion and increased cytsolic Ca. J. Biol. Chem. 260, 13035-13040. 

The other factor affecting the use of organic nitrates is nitrate tolerance, the mechanism of which is unclear. An early explanation of tolerance was thiol depletion [68] but that now seems unlikely as their is an abundance of thiol in most tissue [69]. A more likely explanation is down regulation of the enzymes involved in the biotransformation but few details are available. An interesting suggestion is that GTN induces increased production of superoxide from the vascular wall and tolerance is caused by reaction of NO, produced enzymatically from GTN, with superoxide to give peroxynitrite and then nitrate [70] (Eq. (16)). 

Krokan H, Grafstrom RC, Sundqvist K, et al. 1985. Cytotoxicity, thiol depletion and inhibition of O -methylguanine-DNA methyltransferase by various aldehydes in cultured human bronchial fibroblasts. Carcinogenesis (Lond) 6 1755-1760. 

Among the most studied mechanisms of sulfur mustard toxicity are thiol depletion resulting in intracellular calcium... 

A vicious cycle is thus activated (Figure 4) which amplifies the inflammation stimuli at each cycle. GSH and thiol depletion may thus exert an influence on the immune functions not directly related to their role as antioxidants but as key activators of cell functions. 

The cytotoxic and genotoxic effects of arecoline continue to be investigated. Arecoline was cytotoxic to Hep 2 cells in an acidic medium, and decreased DNA and protein synthesis [350]. The observed cytotoxicity increased on addition of sodium nitrite [350]. Arecoline was found to be clastogenic and genotoxic by observation of chromosome aberrations and sister-chromatid exchanges in Chinese hamster ovary cells [351], It induced unscheduled DNA synthesis in Hep 2 cells [352], Arecoline decreased the survival and proliferation of cultured oral mucosal fibroblasts [353]. Glutathione and cysteine prevented this cytotoxicity, suggesting that thiol depletion could play a role in the toxicity of 117 [353],... 

R.J. Hodgkiss, M.R.L. Stratford and R.R. Watfa, The effect of a-tocopherol and a-tocopheroyl quinone on the radiosensitivity of thiol-depleted mammalian cells, Int. J. Radiat. Oncol. Biol. Phys., 16 (1989) 1297. 

Thiol depletion by culturing normal human foetal lung fibroblasts in cystine-free medium or with thiol-depleting agents induced oxidant accumulation and cell death by apoptosis (Aoshiba et al. 1999). The cell death was prevented by the antioxidants ascorbic acid and catalase. 

Whole rat lung and cultured mouse endothehal cell permeabihty both increased significantly in response to chemical redox imbalance (Zhao et al. 2001). Thiol depletion also resulted in decreased endothelial cadhedrin content and disruption of the endothelial barrier. These deleterious effects of intracellular redox imbalance were blocked by pretreatment with exogenous glutathione. 

The radioprotecting properties of thiols and aminothiols have been known for some time and this is generally attributed to their quenching of radiation-induced radicals such as Oj. Compounds which remove endogenous thiols thus increase radical lifetime and can have sensitizing properties. This mechanism contributes to the action of, for instance, A-ethylmaleimide [90] and any thiol depletion by artificial means should indeed produce enhancement of sensitization [91]. 

Among the most studied mechanisms of sulfur mustard toxicity are thiol depletion, resulting in intracellular calcium imbalance and subsequent cell death alkylation of DNA and other cellular macromolecules lipid peroxidation resulting from sulfur mustard-induced gluthathione depletion and induction of an inflammatory response. The overall mechanism of sulfur mustard toxicity likely involves an interlinking of the aforementioned processes which are briefly described below. 

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