Glutathione, reaction with arene oxides

The intracellular nucleophile glutathione (GSH y-Glu-Cys-Gly) acts as a protective mechanism against electrophilic insults and may be present at concentrations of up to 10 mM [26]. The reaction of glutathione with a non-polar compound bearing an electrophilic carbon, nitrogen or sulfur atom may be mediated enzymatically by glutathione-S-transferase (GST), with typical substrates being species such as arene oxides, quinones and a,P-unsaturated carbonyl compounds. 

As has been stated before, oxirane derivatives are formed as intermediates during metabolic oxidations at carbon-carbon double bonds. These epoxides (arene oxides) undergo spontaneous isomerization to phenols, or enzymic hydration via epoxide hydrase to trans- dihydrodiols, or reaction with reduced glutathione (GSH) via specific GSH-transferases to the corresponding conjugates (Scheme 11), which eventually appear in urine... 

Two important reactions of arene oxides in animal tissue are (1) detoxification and (2) formation of conjugates of arene oxides with purine pyrimidine bases of DNA. For both of these reactions to take place, the arene oxide should have a certain intrinsic stability to survive an aromatization reaction. Reaction with the thiolate bond of glutathione is responsible for detoxification, whereas the extent of involvement of arene oxides in the nucleophilic reactions with nonpolarized nitrogen bases of DNA is directly related to their carcinogenic activity. 

The epoxidation of aldrin to dieldrin is an example of the metabolic formation of a stable epoxide (Figure 10.1A), while the oxidation of naphthalene was one of the earliest understood examples of an epoxide (arene oxide) as an intermediate in aromatic hydroxylation (Figure 10.1B). The arene oxide can rearrange nonenzy-matically to yield predominantly 1-naphthol, can interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or can interact with glutathione -transferase to yield the glutathione conjugate that ultimately is metabolized to a mercapturic acid. This reaction is also of importance in the metabolism of the insecticide carbaryl, which contains the naphthalene nucleus. 

The latter reaction sequence was of importance since addition of the thiol glutathione to arene-oxide intermediates under control of hepatic glutathione-S-epoxide transferase enzyme(s) is a very important metabolic transformation. It would appear probable that most of the structures of the arene oxide-glutathione adducts (premercapturic acids) reported in the literature before 1975 are incorrect with respect to the position of the hydroxy and thioether substituents (they should now be reversed). Addition of thiomethoxide anion to arene oxide 70 may occur via 1,6- and 1,4-addition, although one of these thioether adducts could also be accounted for by the alternative arene-oxide intermediate obtained from an oxygen-walk. Styrene 3,4-oxide (S3) has been observed to react with ethanethiol to yield three adducts which appear to aromatize to three isomeric ethylthiostyrenes without the formation of episulphonium intermediates. ... 

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