Epoxides glutathione conjugation

T.A (1975). Oxidative metabolism of aflatoxin B. observations on the fornnation of epoxide-glutathione conjugate. Chem.-Biol. Interactions. H, 301-305. 

Residues of PCBs in animal tissues include not only the original congeners themselves, but also hydroxy metabolites that bind to cellular proteins, for example, transthyretin (TTR Klasson-Wehler et al. 1992 Brouwer et al. 1990 Fans et al. 1993). Small residues are also found of methyl-sulfonyl metabolites of certain PCBs (Bakke et al. 1982, 1983). These appear to originate from the formation of glutathione conjugates of primary epoxide metabolites, thus providing further evidence of the existence of epoxide intermediates. Further biotransformation, including methylation, yields methyl-sulfonyl products that are relatively nonpolar and persistent. 

In terrestrial animals, the excreted products of PAHs are mainly conjugates formed from oxidative metabolites. These include glutathione conjugates of epoxides, and sulfate and glucuronide conjugates of phenols and diols. 

Together with glutathione conjugation, hydration is a major pathway in the inactivation and detoxification of arene oxides. Exceptions to this rule will be treated when discussing polycyclic aromatic hydrocarbons. Arene oxides are good substrates for microsomal EH, as evidenced in Table 10.1, where hydration of selected arene oxides, alkene oxides, and cy-cloalkene oxides by purified rat liver epoxide hydrolase is compared. The hy- ... 

Thiol conjugation Epoxides Glutathione S-transferases (glutathione or N-acetylcysteine) Glutathione or N-acetyl cysteine thioethers... 

Glutathione conjugation Glutathione (GSH) GSH-S-transferase (cytosol, microsomes) Epoxides, arene oxides, nitro groups, hydroxylamines Acetaminophen, ethacrynic acid, bromobenzene... 

The oxidation of naphthalene was one of the earliest examples of an epoxide as an intermediate in aromatic hydroxylation. The epoxide can rearrange nonenzymatically to yield predominantly 1-naph-thol, interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or interact with glutathione S-transferase to yield the glutathione conjugate, which is ultimately metabolized to a mer-capturic add. 

The further metabolism of suitably stable epoxides may occur, with the formation of dihydrodiols as discussed later. Dihydrodiols may also be further metabolized to catechols. Other products of aromatic hydroxylation via epoxidation are glutathione conjugates. These may be formed by enzymic or nonenzymic means or both, depending on the reactivity of the epoxide in question. 

Figure 7.2 The metabolic activation of benzo[a]pyrene by cytochrome P-450 1A1 to a diol epoxide metabolite, a mutagen. This is believed to be the ultimate carcinogenic metabolite. Other routes of metabolism also catalyzed by cytochrome P-450 give rise to the 9,10, and 4,5 oxides and subsequent metabolites namely phenols, diols, and glutathione conjugates. The reactive site (carbon atom) on the metabolite is indicated.

Gaigas et al. (1995) have developed a physiological toxicokinetic model of acrylonitrile in rats which includes the behaviour of CEO. In-vitro kinetic studies of the metabolism of both acrylonitrile and CEO showed that epoxidation to CEO is saturable, while glutathione conjugation of acrylonitrile follows first-order kinetics. The model combines these kinetic parameters with tissue partition data to allow simulation of the urinary excretion of acrylonitrile metabolites and the fonnation of haemoglobin adducts (see below). The model has been further refined by Kedderis et al. (1996) to predict the behaviour of acrylonitrile and CEO after inhalation exposure to acrylonitrile. 

Raney KD, Meyer DJ, Ketterer B et al. (1992) Glutathione conjugation of aflatoxin B1 exo-and endo-epoxides by rat and human glutathione S-transferases. Chem Res Toxicol 5 470-478... 

Figure 13.7. Glutathione conjugation to reactive metabolites by GSTs. Ultimate carcinogens such as benzo[a]pyrene 7,8-diol 9,10-epoxide and aflatoxin B1 8,9-epoxide are glutathione-conjugated for detoxification by GSTM1, GSTp, and GST A, respectively. Lipid peroxidation product 4-hydroxy-2-nonenal is preferentially detoxified by GSTA.

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