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Figure 24 The metabolic pathway from arene oxides (74) to aromatic mercapturic acids (77) is presented here; the first product of addition is 75, which dehydrates and aromatizes to 76 before being cleaved and N-acetylated. Also shown here is the logical pathway leading from valdecoxib (78) to its methyl sulfone conjugate (79).

medicinal viewpoint since anticancer agents such as methylformamide appear to work by undergoing activation to isocyanates and then to the glutathione conjugate.

An important role of GSH is in the conjugation of arene oxides, particularly those with slower rearrangement to the phenol and which are poor substrates of epoxide hydrolase (see Section 5.06.2.3.2 and Figure 8). The first reaction is again a nucleophilic addition to the epoxide (74, Figure 24), the target carbon atom here being sp3-hybridized state. The resulting nonaromatic conjugate (75) then dehydrates to an aromatic GSH conjugate (76), followed by a cascade leading to the mercapturic acid (77) as also shown in Figure 22. This is a common reaction of metabolically produced arene oxides, as documented for naphthalene and numerous drugs and xenobiotics containing a phenyl moiety. Note that the same reaction can also occur readily for epoxides of olefins.

An interesting example of GSH addition to an arene oxide is found in the metabolism of the COX-2 inhibitor valdecoxib (78, Figure 24).128 When administered to mice, the compound was almost completely metabolized by phase I and phase II reactions, with 16 metabolites being identified in blood, urine, and feces. One of these was the methyl sulfone derivative 79, whose formation can only be understood by epoxidation, GSH conjugation, mercapturic acid formation, b-lyase C-S cleavage to form the free thiol, S-methylation, and finally S-oxygenation (Figure 22).

Glutathione conjugation by a mechanism of nucleophilic substitution (addition-elimination) appears more frequent with industrial xenobiotics than with drugs. Thus, compounds having an activated alkyl moiety of general structure 80 (Figure 25) become electrophilic when X is an electron-withdrawing leaving group such as a halogen atom or a sulfate ester group of metabolic origin. Such a reaction occurs for example at the -CHCl2 group of chloramphenicol. At first sight, the reaction of glutathione with alkylating cytostatic drugs having a nitrogen mustard group (e.g., melphalan 81, Figure 25) to yield a conjugate such as 83 occurs by a substitution reaction. However, this is true only if one neglects the intermediate aziridinium ion (82), which is formed by chloride elimination independently of the presence of GSH. In other words, the real reaction is again one of nucleophilic addition.129

With good leaving groups (e.g., halogen, nitro, sulfoxide, sulfone), nucleophilic aromatic substitution reactions also occur at aromatic rings containing additional electron-withdrawing substituents and/or heteroatoms (i.e., compounds 84, Figure 25).

Acyl halides (85; X = F Cl, Br) are highly reactive industrial compounds, but some can also arise as toxic metabolic intermediate. Their detoxification by glutathione to yield a thioester type of conjugate is a highly effective mechanism of protection. A good example is provided by phosgene (O = CCl2), an extremely toxic metabolite of chloroform which is inactivated to the diglutathionyl conjugate O = C(SG)2.

While not nearly as reactive as acyl halides, acyl-glucuronides (85, Figure 25; X = O-Gluc) can nevertheless cause damage by forming adducts with proteins (see Section 5.06.3.4.2). Interestingly, they can also be conjugated with and detoxified by GSH. This has been demonstrated, for example, with zomepirac, an NSAID of the arylacetic acid class.

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