Epoxides cellular effects

Conversion of epoxides (arene oxides) into phenols is spontaneous. The conversion of epoxides into dihydrodiols is catalyzed by EH (EC 4.2.1.63). Hydroxyl containing PAHs can act as substrates for conjugases (C) (UDP glucuronsyl transferase (EC 2.4.1.17) and phenol sulphotransferase (EC 2.8.2.1)). This pathway usually leads to inactive excretable products. Epoxides are scavenged by GSH and the reaction is catalyzed by GSHt (EC 2.5.1.18). When GSH is depleted and/or the other pathways are saturated, epoxides of dihydrodiols (particularly 7,8-diol-9,10-epoxides in the case of BP) and phenol metabolites react with cellular macromolecules such as DNA, RNA, and protein. If repair mechanisms are exceeded the detrimental effects of PAH may result. 

The body s natural defenses against overenthusiastic oxidation include a-lipoic acid, reduced glutathione, ascorbic acid, the tocopherols, the carotenoids, and a number of enzymes such as epoxide hydrolase and the like. Very efficient DNA repair systems also operate defensively. These various means are remarkably effective, but DNA assault is continuous, cumulative, and implacable. Thus, many degenerative diseases are associated with aging because of the gradual slippage in functional fidelity of cellular machinery which occurs with age. 

Acrylonitrile owes some of its toxicity to cyanide generation, which inhibits cellular respiration. Preinduction of microsomal mixed function oxidase (MFO) with Arochlor 1254 greatly enhanced the toxicity of acrylonitrile and caused a threefold increase in cyanide levels in rats. Therefore, metabolic activation appears to be necessary in the toxicity of acrylonitrile. The direct reaction of acrylonitrile with the SH groups of proteins and its epoxide metabolite are also expected to be responsible for its effects. 

Oltipraz [4-methyl-5-(2-pyrazinyl)-l, 2-dithiole-3-thione] (OPZ), a synthetic derivative of 1, 2-dithiole-3-thione, has been extensively investigated for its chemopreventive properties first developed as an antischistosomal agent, this compound was found to increase cellular thiol levels and to induce enzymes involved in the maintenance of reduced glutathione (GSH) pools and in detoxification of electrophilic intermediates. Induction of phase 2 enzymes such as GSTs, epoxide hydrolases, and NADP(H) quinone reductases was considered to represent the key mechanism of chemoprotection of OPZ. More recently this compound was also found to modulate phase 1 enzymes, antioxidant enzymes, and other inactivating proteins, thereby indicating that its chemoprevention mechanism(s) are more complex than first envisaged. In this chapter, current information about the effects of OPZ on phase 1 and phase 2 enzymes is presented. 

Although the PAHs can result in a direct toxic effect, the major concern resides in the formation of reactive metabolites such as epoxides and dihydrodiols, which can bind to the genetic material and to the cellular proteins (Albers, 2002). 

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). 

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