Figure 143

The role of GSH in DEB toxicity provides a plausible background to envisage oxidative stress-dependent GSH depletion and, especially, decreased GST activity as possible contributory factors affecting the detoxification potential of cells and individual susceptibility to DEB toxicity. This view was corroborated by a study in which pretreatment with phorone, a well-known intracellular glutathione depletor, was found to enhance DEB cytotoxicity, consistent with an active role played in vivo by the GSH-detoxifying system.53

Besides GST, another GSH-dependent enzyme has been implicated in the detoxification of DEB-induced DNA damage, i.e., GSH peroxidase (GSH-Px).52 Studies of the effect of glutathione peroxidase (GSH-Px) in mammalian red blood cells (RBC) on spontaneous and DEB-induced sister chromatid exchange (SCE) in primary Big Blue mouse (BBM1) and Big Blue rat (BBR1) fibroblasts indicated that both GSH-Px and RBC alone or in combination were effective in significantly reducing DEB-induced SCE in both mouse and rat fibroblasts.52 These results raise the intriguing possibility that H2O2 may be involved in DEB toxicity.53

In addition to conjugation with GSH, a possible transformation route of DEB is hydrolysis.54 A comparative screening of the microsomal hydrolysis of 1,2:3,4-diepoxybutane (BDE) using tissues of rats, mice, and humans was found to give two main metabolites, erythritol and anhydroerythritol. It is tempting to speculate that diol and polyol products of DEB hydrolysis, though expectedly inactive per se, may be sources of cytotoxic aldehydes (e.g., glyoxal) following oxidation and retroaldol reactions under oxidative stress conditions.

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Natural Detox

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