Arene oxide substrates

Together with glutathione conjugation, hydration is a major pathway in the inactivation and detoxification of arene oxides. As a rule, these are good substrates of microsomal epoxide hydrolase. But when reading the literature, the

Figure 7 A simplified model showing that the nucleophilic attack of the substrate is mediated by a carboxylate group in the catalytic site to form an ester intermediate. Only in the second step is the intermediate hydrolyzed by an activated water molecule, leading to enzyme reactivation and product liberation. (Reproduced from Testa, B.; Mayer, J. M. Hydrolysis in Drug and Prodrug Metabolism - Chemistry, Biochemistry and Enzymology; Wiley-Verlag Helvetica Chimica Acta: Zurich, Switzerland, 2003, with the kind permission of the copyright owner, Verlag Helvetica Chimica Acta in Zurich.)

variety of intertwined metabolic pathways centered around arene oxides is not always easy to grasp. The general scheme presented in Figure 8 should contribute to clarify the metabolic context of arene oxides. These arise by CYP-catalyzed oxidation of arenes (see 5.05 Principles of Drug Metabolism 1: Redox Reactions) and are a crossroads to a number of metabolic routes, namely: (1) conjugations, (2) adduct formation, (3) proton-catalyzed isomerization to phenols followed by oxidation to diphenols and even to quinones, and (4) EH-catalyzed hydration to trans-dihydrodiols. The latter reaction is the topic of this section.

In phenyl and naphthyl rings, the proton-catalyzed isomerization of epoxides to phenols is an extremely fast reaction that markedly reduces the likelihood of the epoxide being hydrated by epoxide hydrolase. This chemical instability decreases for chemicals with three or more fused rings, but such compounds are no longer of medicinal interest and will not be discussed here. Yet, despite the high reactivity of benzene epoxides, the characterization of a dihydrodiol metabolite has been achieved for a limited number of phenyl-containing drugs, and particularly for neurodepressant drugs such as hypnotics (e.g., glutethimide) and antiepileptics (e.g., ethotoin and phenytoin).

For example, phenytoin (diphenylhydantoin) is a good substrate of cytochrome P450. Incubations with rat liver 9000 g supernatant produced the ^ara-phenol (4'-hydroxy-phenytoin) as the major metabolite, and the dihydrodiol in smaller proportions. Interestingly, aromatic oxidation of phenytoin in humans and other mammals except the dog occurs almost exclusively at the pro-S phenyl ring, the ^ara-phenol having the (S)-configuration at C5, i.e., (5S)-5-(4-hydroxyphenyl)-5-phenylhydantoin. The dihydrodiol similarly has the (S)-configuration at its C5, while its C3' and C4' atoms in the oxidized phenyl ring have the trans-(R;R)-configuration, i.e., (5S)-5-[(3R;4R)-3,4-dihydroxy-1, 5-cyclohexadien-1-yl]-5-phenylhydantoin (14, Figure 9) (for a review see5).

A more recent example is that of rofecoxib, a potent and selective cyclooxygenase-2 (COX-2) inhibitor. In rats and dogs, phenyl oxidation produced 4'-hydroxy-rofecoxib and rofecoxib-3',4'-dihydrodiol (15, Figure 9) as urinary metabolites of intermediate quantitative importance.29

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