Chemicals glutathione depletion

Fonnum, F., and Lock, E. A. The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurons Exemplified with toxic effects on cerebellar granule cells. J. Neurochem. 88, 513-531, 2004. 

Okada et al. examined the effects of TBT on cellular content of glutathione (GSH) in rat thymocites using a flow cytometer and 5-chloromethylfluorescein diacetate, a fluorescent probe for monitoring the change in the cellular content of GSH. TBT at nanomolar concentrations reduced the cellular content of GSH. There is an important implication on the TBT-induced depletion of cellular GSH since GSH has an important role in protecting the cells against oxidative stress and chemical and metal intoxications. TBT-induced decrease in cellular content of GSH in thymocytes may increase the vulnerability of the immune system. ° ... 

Furthermore, depletion of hepatic GSH induced chemically or by fasting augmented hepatic I/R-induced enzyme release and promoted lipid peroxidation (Jennische, 1984 Stein et al., 1991) Benoit et al. (1992) have used portacaval-shunted rats as a model of chronic hepatic ischaemia, and were able to show decreases in total levels of SOD and xanthine dehydrogenase, but no significant change in catalase or glutathione peroxidase. 

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. 

Lam et al. (1985) found a dose-related depletion of glutathione in the nasal respiratory mucosa of rats after exposure to 0.1-2.5 ppm of acrolein for 3 hours. This finding is consistent with a chemical reaction leading to the formation of a glutathione-acrolein adduct. 

Depletion of cellular GSH has been widely studied with hundreds of chemicals including APAP and bromobenzene. These studies demonstrated very clearly that bioactivation followed by GSH adduct formation causes depletion of cytosolic glutathione and oxidative stress as indicated by indicators including enhanced levels of GSSG, lipid peroxidation, and loss of membrane integrity. 

There may tdso be conjunctivitis with vascularization of the cornea tmd opacity of the lens. This is the only lesion for which we know a possible hio-chemical basis - glutathione is important in maintaining the normal clarity of crystallin in the lens, and glutathione reductase is a flavoprotein that is paiticulaily sensitive to rihoflavin depletion. 

No information was located regarding toxic interactions of 1,1-dichloroethane with other xenobiotics. Evidence exists to indicate that 1,1- dichloroethane is detoxified by glutathione (Colacci et al. 1985). Thus, it is likely that other substances that deplete glutathione stores such as other chlorinated hydrocarbons (e.g. 1,1-dichloroethane and 1,2-dichloroethane), acetaminophen, and bromobenzene may enhance the toxicity of 1,1- dichloroethane. Substances that alter the activity of the microsomal enzymes that are responsible for the metabolism of 1,1 -dichloroethane may also affect the toxicity of this chemical. For example, it has been shown that ethanol increases the metabolism of 1,1 -dichloroethane in vitro (Sato et al. 1980). 

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... 

---