Glutathione destruction

BIO. Beutler, E., Robson, M., and Buttenwieser, E., The mechanism of glutathione destruction and protection in drug sensitive and nonsensitive erythrocytes. In vitro studies. J. Clin. Invest. 38, 617-628 (1957). 

As an example, acetaminophen (APAP) in overdose has been used by several groups to identify hepatotoxicity biomarkers in mice. APAP-induced hepatotoxicity is characterized by hepatic centrilobular necrosis and hepatitis. APAP biotransformation by Phase I enzymes leads to the formation of the reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which can deplete glutathione and form adducts with hepatic proteins (see Section 15.2). Protein adduction primes the hepatocytes for cytokines released by activated macrophages (Kupffer cells) and/or destructive insults by reactive nitrogen species. Although necrosis is recognized as the mode of cell death in APAP overdose, the precise mechanisms are still being elucidated [152]. 

Allyl chloride is presumed to be metabolized to allyl alcohol, which could then be further metabolized via two pathways to form either acrolein or glycidol, from which a variety of metabolites could result. Metabolites identified in rat urine are 3-hydroxy-propylmercapturic acid and allyl mercapturic acid and its sulfoxide. Allyl glutathione and S-allyl-L-cysteine have been detected in the bile of dosed rats. In-vitro metabolism of allyl chloride results in haem destruction in microsomal cytochrome P450 (lARC, 1985). 

Selenium is a trace element essential to life. For example, the selenium-containing enzyme glutathione peroxidase catalyzes the destruction of peroxides (ROOH) that are harmful to cells. Conversely, at high concentration, selenium can be toxic. 

Chromium(VI) readily enters erythrocytes, where it is reduced to chromium(III) by glutathione, and chromium(III) is essentially trapped within erythrocytes, where it binds to proteins, primarily hemoglobin. This may explain the fact that chromium shows little toxicity at sites distant from administration sites (De Flora and Wetterhahn 1989). The chromium(ni) trapped within the erythrocytes would be released upon natural destruction of the erythrocyte and excreted in the urine. 

Fig. 2.8. Factors controlling the production of free radicals in cells and tissues (Rice-Gvans, 1990a). Free radicals may be generated in cells and tissues through increased radical input mediated by the disruption of internal processes or by external influences, or as a consequence of decreased protective capacity. Increased radical input may arise through excessive leukocyte activation, disrupted mitochondrial electron transport or altered arachidonic acid metabolism. Delocalization or redistribution of transition metal ion complexes may also induce oxidative stress, for example, microbleeding in the brain, in the eye, in the rheumatoid joint. In addition, reduced activities or levels of protectant enzymes, destruction or suppressed production of nucleotide coenzymes, reduced levels of antioxidants, abnormal glutathione metabolism, or leakage of antioxidants through damaged membranes, can all contribute to oxidative stress.

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