Epoxide oxidative stress

Oxidative stress and covalent binding to macromolecules. Oxidation to the epoxide occurs via a tetrahedral intermediate, which can form either an epoxide or a phenol directly (see the scheme below). The epoxide can covalently bind nucleophiles, such as DNA or proteins, to open up the epoxide to a phenol and make toxic covalent adducts. The phenols can be further oxidized to bisphenols, which can in turn form quinones. Quinones can cause serious oxidative damage to cells through radical pathways, or can alkylate N- or S-nucleophiles, such as glutathione and glycine. 

Several oxysterol classes present in oxLDL appear to be cytotoxic toward fibroblasts, ECs, and vascular smooth muscle cells, especially 7-hydroperoxycholes-terol (7-OOH-chol), 7P- and 7a-hydroxycholesterol (7-OH-chol), 7-ketocholesterol (7-keto-chol), and cholesterol epoxides (epoxy-chol). 7p-OOH-chol, a precursor of hydroxyl- and keto-oxysterols, was reported to be the most toxic. During LDL oxidation 7P-OOH-chol was produced in three to five times higher quantities than 7a-OOH-chol, other oxysterols and even hydroxy-nonenal, which is one of the most abundant lipid oxidation products. Cytotoxicity of oxysterols was connected to increased cellular oxidative stress. Some studies suggest that oxysterols are even involved in oxidative stress induction. Animal models indicate that dietary oxysterols can significantly decrease glutathione levels and increase expression of glutathione peroxidase and superoxide dismutase. In apolipoprotein-deficient mice, the NADPH-oxidase activity was induced by 7-keto-chol, 7p-OH-chol, and Sp,6P-epoxy-chol. The increased activity of NADPH oxidase yields more superoxide anions that amplify oxidative stress. 

Class III, the reactive chemicals, include epoxides, aldehydes, aziridines, quinones (generally, all alkylating agents) (Hermens Verhaar, 1995). These chemicals (or their activated metabolites) react covalently with nucleophilic sites in cellular biomacromolecules (e.g., through nucleophilic substitution, Michael-type addition, or Schiff-base reactions) or gain an oxidative stress through redox cycling to derive toxic effects (Bradbury et al., 2003). 

At least two systems can be cited as catalysts of peroxide oxidation the first are the iron (III) porphyrins (44) and the second are the Gif reagents (45,46), based on iron salt catalysis in a pyridine/acetic acid solvent with peroxide reagents and other oxidants. The author s opinion is that more than systems for stress testing these are tools useful for the synthesis of impurities, especially epoxides. From another point of view, they are often considered as potential biomimetic systems, predicting drug metabolism. Metabolites are sometimes also degradation impurities, but this is not a general rule, because enzymes and free radicals have different reactivity an example is the metabolic synthesis of arene oxides that never can be obtained by radical oxidation. 

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