GSH depletion

The effect of cellular GSH depletion on /wa/K has also been studied using this model. Guinea-pig ventricular myocytes prepared from DEM-treated animals have been used to determine the effect of glutathione depletion on /xa/K- Myocytes prepared from DEM-treated animals showed a similar profile of glutathione content modification to that previously described in experiments using sarcolemmal homogenates. GSH levels in DEM-treated were reduced from a control value of 0.2 0.04 to 0.02 0.01 nmol/1 X10 cells. Jni/k at 0 mV was reduced from a control value of 1.1 0.12 to... 

Enhancement of lipid peroxidation and GSH depletion proportional to the iron content... 

Distribution of acrylonitrile (ACN) in tissues of control and glutathione (GSH) depleted B6C3F1 mice... 

Botti B, Franceschini V, Tomasi A, et al. 1989. Mechanistic aspects of 1,2-dibromoethane-induced mitochondrial GSH depletion in vitro. Adv Biosci 76 99-105. 

The diterpenes andrographolide, andrographiside and neoandro-grapholide isolated from A. paniculata were also investigated for their protective effects on hepatotoxicity induced in mice by carbon tetrachloride or /ert-butylhydroperoxide ( BHP) intoxication by Kapil et pretreatment of mice with the individual diterpenes at a dose of 100 mg/kg, i.p. for 3 consecutive days were observed to produce significant reduction in malondialdehyde formation, reduced glutathione (GSH) depletion and... 

However, the adverse effects of APAP bioactivation are not observed until high doses are administered, where there is sufficient depletion of natural reserves of antioxidants, for example, reduced glutathione (GSH). Depletion of GSH exacerbates arylation of cellular proteins by NAPQI and amplifies oxidative stress from ROS, eventually leading to a drop in cellular ATP levels and cell death. Hence it is not the advent of covalent binding of reactive intermediates that is solely responsible for APAP toxicity, but rather a combination of events in which protein binding plays an important role. 

The role of GSH in cellular protection (see below) means that if depleted of GSH, the cell is more vulnerable to toxic compounds. However, GSH is compartmentalized, and this compartmentalization exerts an influence on the relationship between GSH depletion or oxidation and injury. The loss of reduced GSH from the cell leaves other thiol groups, such as those in critical proteins, vulnerable to attack with subsequent oxidation, cross-linking, and formation of mixed disulfides or covalent adducts. The sulfydryl groups of proteins seem to be the most susceptible nucleophilic targets for attack, as shown by studies with paracetamol (see chap. 7), and are often crucial to the function of enzymes. Consequently, modification of thiol groups of enzyme proteins, such as by mercury and other heavy metals, often leads to inhibition of the enzyme function. Such enzymes may have critical endogenous roles such as the regulation of ion concentrations, active transport, or mitochondrial metabolism. There is... 

Studies using a combination of techniques have revealed a sequence of events starting within 15 minutes of a toxic dose, with GSH depletion and mitochondrial changes detected by electron microscopy. The depletion of GSH leaves the mitochondria and the cell, in general, vulnerable. Mitochondria without adequate GSH will generate ROS, which will cause more... 

Cephaloridine will inhibit organic ion transport in the kidney and, this is preceded by the lipid peroxidation. Antioxidants block both events, suggesting that they are related. GSH depletion is a very early event, occurring before lipid peroxidation is detectable. 

Since GSH conjugation is an important pathway in butadiene metabolism, several laboratories have investigated the GSH-depleting effect of butadiene. 

Stenins, U., Warholm, M., Raimug, A., Walles, S., Lundberg, I. Hdgberg, J. (1989) The role of GSH depletion and toxicity in hydroquinone-induced development of enzyme-altered foci. Carcinogenesis, 10, 595-599... 

Imberti. R.. Mapelli. A.. Colombo. P, Richelmi. P, Berte, F. Bellomo, G. (1990) 1,2-Dichloro-propane (DCP) toxicity is correlated with DCP-induced glutathione (GSH) depletion and is modulated by factors affecting intracellular GSH. Arch. Toxicol., 64,459-465... 

Some of the sensitizing (and cytotoxic) effects of the nitro compounds can be attributed to GSH depletion. Activated chlorine maybe replaced by GS" [reaction (89) Wardman 1982 Stratford et al. 1983)], but the reaction is much more general. For example, the 2-nitroimidazoles react with GS by N02 release. These reactions are slow, but are considerably speeded up by glutathione-S-transferase (Wardman et al. 1973). 

Pereira C. M. F. and Resende de Oliveira C. (1997). Glutamate toxicity on a PC12 cell line involves glutathione (GSH) depletion and oxidative stress. Free Radic. Biol. Med. 23 637-647. 

Cleavage of the carbon backbone is reported to be mediated by hydrolases [63]. However, there are no indications that this side-reaction proceeds enzymatically. Instead formation of retro-Claisen products 12 and 13 proceeds via GSH addition to the carbonyl center in 2. The active role of GSH was demonstrated with GSH-depleted cells. After treatment with N-ethyl maleimide (NEM) [64] no retro-Claisen product was detectable. The same applied for NEM-treated cell liquor. 

Figure 7.10 A model of GSH depletion and neurological disease. GSH is known to play an analogous role in other tissues.

Type II deiodinase activity is low in unsupplemented tissue homogenates but is stimulated by DTT [71-74,82,83] and to a lesser extent also by GSH [72]. The DTT concentrations required for maximal enzyme stimulation in the CNS and pituitary seem higher than in BAT and also than those necessary for the type I deiodinase in liver and kidney. Kinetic analysis of the deiodination of varying substrate (T4, rT3) concentrations at different cofactor (DTT) levels have indicated a sequential reaction mechanism for the type II deiodinase [73,82,83]. This is very suggestive of the formation of a ternary enzyme-substrate-cofactor complex in the catalytic process [82], The physiological cofactor of the type II deiodinase has not been identified but it has been observed that GSH depletion with diamide or diethylmaleate impairs T4 to T3 conversion in GH3 pituitary tumor cells [93]. 

Slott V, Hales BF. 1985. Effect of glutathione (GSH) depletion by buthionine sulfoximine (BSO) on the in vitro teratogenicity and embryolethality of acrolein (AC). Teratology 31 33A. 

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