Most known cases of glutathione conjugation are nucleophilic attacks of electron-deficient carbon atoms, but attack of a nitrogen atom (e.g., in an aromatic nitroso group) or a sulfur atom (in thiols) is also documented. Very often, the target carbon atom is sp3- or sp2-hybridized, but a few examples document the reactivity of sp-hybridized carbons. From a mechanistic viewpoint, it may be convenient to subdivide glutathione conjugations into nucleophilic additions and nucleophilic substitutions (i.e., addition-eliminations).4,37,40
Nucleophilic additions can involve metabolites arising from oxidation reactions, but they can also occur as primary metabolic reactions. Frequent cases of GSH addition are to a,b-unsaturated carbonyls, a typical xenobiotic substrate being the toxin acrolein (CH2=CH-CHO). Attack occurs at the activated CH2 group. The mechanism of GSH addition to a,b-unsaturated carbonyls is summarized in Figure 23 with the diuretic drug ethacrynic acid (68), whose glutathione conjugate (69) has been known for many years. As shown, the exomethylene is electron deficient and is thus the obvious target of glutathione.
Quinones (ortho- and para-) and quinoneimines are structurally very similar to a,b-unsaturated carbonyls. They react with glutathione by two distinct and competitive routes, one of which is a reduction to the hydroquinone or aminophenol, where GSH does not react covalently with the substrate but emerges in the oxidized form (GSSG). The other route is relevant to the present context, being a nucleophilic addition to form a conjugate. The reaction has physiological significance since endogenous metabolites such as quinone metabolites of estrogens are conjugated to glutathione. A medicinal example is provided by the toxic quinoneimine metabolite (71, Figure 23; see 5.05 Principles of Drug Metabolism 1: Redox Reactions; 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs) of paracetamol (30). Its glutathione conjugate (71) is not excreted as such in humans dosed with the drug, but as the mercapturic acid (67, Figure 22). The reaction is one of major detoxification, the quinoneimine being extremely hepatotoxic and resulting in liver necrosis, liver failure, and even death when produced at levels and rates that oversaturate the GSH conjugation pathway. Nevertheless, the GSH conjugation of quinones and quinonimines is not always a reaction of detoxification, as some of these conjugates are known to undergo further transformations leading to reactive products.126
The addition of glutathione to isocyanates and isothiocyanates (72, Figure 23; X = O and S, respectively) has received some attention due in particular to its reversible character.127 Substrates of the reaction are xenobiotics such as the infamous toxin methyl isocyanate, whose glutathione conjugate (73) behaves as a transport form able to carbamoylate various macromolecules, enzymes, and membrane components. The reaction is also of interest from a
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