Glutathione oxidized, formation

The key to hexavalent chromium s mutagenicity and possible carcinogenicity is the abiHty of this oxidation state to penetrate the cell membrane. The Cr(VI) Species promotes DNA strand breaks and initiates DNA—DNA and DNA-protein cross-links both in cell cultures and in vivo (105,112,128—130). The mechanism of this genotoxic interaction may be the intercellular reduction of Cr(VI) in close proximity to the nuclear membrane. When in vitro reductions of hexavalent chromium are performed by glutathione, the formation of Cr(V) and glutathione thiyl radicals are observed, and these are beHeved to be responsible for the formation of the DNA cross-links (112). 

Jaeschke, H. (1990). Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo-, the protective effect of allopurinol. J. Pharmacol Exp. Ther. 255, 935-941. 

Phenacetin Analgesic NH-COCH3 9 O-CHsCHg 0-Dealkylation, N-hydro-xylation and arene oxide formation Glutathione conjugates 0-Dealkylation (Cunninghamella elegans) [97]... 

DeLucia, A. J., M. G. Mustafa, M. Z. Hussain, and C. E. Cross. Ozone interaction with rodent lung. III. Oxidation of reduced glutathione and formation of mixed disulfides between protein and nonprotein sulfhydryls. J. Gin. Invest. 55 794-802, 1975. 

Figure 4.60 Conjugation of naphthalene-1,2-oxide with glutathione and formation of naphthalene mercapturic acid.

Figure 1. Proposed metabolic pathways of dichloroacetylene by glutathione conjugate formation and cytochrome P450 oxidation...

Little is known about the mode of action of hydra-zinecarboxamide-derived fungicides. Since diazene formation is involved in the fungitoxic action of phenyl-thiosemicarbazide (2 2) and is implicated in a glutathione-oxidation mechanism to account for fungi-toxicity of similarly structured compounds (2 1 ), it is conceivable that diazenes described in this study may well play a critical role in the action of fluorine-substituted hydrazinecarboxamide fungicides and perhaps larvicides as well. 

As well as the formation of NAPQI there are various other possible metabolic pathways, including deacetylation and radical formation, which may or may not play a role in the hepatotoxicity. The importance of and interrelationships between covalent binding to particular hepatic proteins, cyclical oxidation and reduction of glutathione, oxidation of protein thiol groups and the intracellular calcium level are currently unclear. These events are not mutually exclusive and so it is possible that all are a series of necessary events occurring at particular stages in the development of paracetamol hepatotoxicity. However, covalent binding to protein is still believed to be the important event in the toxicity. 

FIGURE 9. A comparison of the apoptotic response produced by ascorbic acid treatment compared to other antioxidant treatments. SCC-25 cells were stained for nucleosome formation as shown in Fig. 8. The relative number of apoptotic cells per 100 cells was counted. The treatment groups were 1) canthaxanthin, 2) p-carotene, 3) retinyl palmitate, 4) a-tocopherol acid succinate, 5) ascorbic acid, 6) glutathione (reduced), and 7) glutathione (oxidized). The treatment doses were 20, 10, and 1.25 fxM. 

This thiol-disulfide interconversion is a key part of numerous biological processes. WeTJ see in Chapter 26, for instance, that disulfide formation is involved in defining the structure and three-dimensional conformations of proteins, where disulfide "bridges" often form cross-links between q steine amino acid units in the protein chains. Disulfide formation is also involved in the process by which cells protect themselves from oxidative degradation. A cellular component called glutathione removes potentially harmful oxidants and is itself oxidized to glutathione disulfide in the process. Reduction back to the thiol requires the coenzyme flavin adenine dinucleotide (reduced), abbreviated FADH2. 

If cellular redox state, determined by the glutathione status of the heart, plays a role in the modulation of ion transporter activity in cardiac tissue, it is important to identify possible mechanisms by which these effects are mediated. Protein S-,thiolation is a process that was originally used to describe the formation of adducts of proteins with low molecular thiols such as glutathione (Miller etal., 1990). In view of the significant alterations of cardiac glutathione status (GSH and GSSG) and ion-transporter activity during oxidant stress, the process of S-thiolation may be responsible for modifications of protein structure and function. 

It was recently reported that. >97% of BaP 4,5-epoxide metabolically formed from the metabolism of BaP in a reconstituted enzyme system containing purified cytochrome P-450c (P-448) is the 4S,5R enantiomer (24). The epoxide was determined by formation, separation and quantification of the diastereomeric trans-addition products of glutathione. Recently a BaP 4,5-epoxide was isolated from a metabolite mixture obtained from the metabolism of BaP by liver microsomes from 3-methylcholanthrene-treated Sprague-Dawley rats in the presence of the epoxide hydrolase inhibitor 3,3,3-trichloropropylene oxide, and was found to contain a 4S,5R/4R,5S enantiomer ratio of 94 6 (Chiu et. al., unpublished results). However, the content of the 4S,5R enantiomer was <60% when liver microsomes from untreated and phenobarbital-treated rats were used as the enzyme sources. Because BaP 4R,5S-epoxide is also hydrated predominantly to 4R,5R-dihydro-... 

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