Cytochrome P450 Can Epoxidize an Oxepin to a Reactive 2,3-Epoxyoxepin Intermediate: Potential Insights into Metabolic Ring-Opening of Benzene.

Holly M. Weaver-Guevara,Arthur Greenberg,Ryan W. Fitzgerald,Noah A. Cote

doi:10.3390/molecules25194542

Holly M. Weaver-Guevara, Arthur Greenberg + Show 2 more

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https://doi.org/10.3390/molecules25194542

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Abstract

Dimethyldioxirane epoxidizes 4,5-benzoxepin to form the reactive 2,3-epoxyoxepin intermediate followed by very rapid ring-opening to an o-xylylene that immediately isomerizes to the stable product 1H-2-benzopyran-1-carboxaldehyde. The present study demonstrates that separate incubations of 4,5-benzoxepin with three cytochrome P450 isoforms (2E1, 1A2, and 3A4) as well as pooled human liver microsomes (pHLM) also produce 1H-2-benzopyran-1-carboxaldehyde as the major product, likely via the 2,3-epoxyoxepin. The reaction of 4,5-benzoxepin with cerium (IV) ammonium nitrate (CAN) yields a dimeric oxidized molecule that is also a lesser product of the P450 oxidation of 4,5-benzoxepin. The observation that P450 enzymes epoxidize 4,5-benzoxepin suggests that the 2,3-epoxidation of oxepin is a major pathway for the ring-opening metabolism of benzene to muconaldehyde.

Highlights

Benzene (1) is a very widespread environmental contaminant and human carcinogen with a complex metabolic fate (Scheme 1)
The present study makes a comparison between the oxidative metabolism of benzene through benzene oxide/oxepin with that of a “non-natural metabolite” of naphthalene: 4,5-benzoxepin
P450 enzymes

Summary

Introduction

Benzene (1) is a very widespread environmental contaminant and human carcinogen with a complex metabolic fate (Scheme 1). The discovery [1] of the equilibrium between benzene oxide (2). Oxepin (6) laid the groundwork for the study by Davies and Whitham [2] in which they oxidized oxepins by employing meta-chloroperbenzoic acid (m-CPBA), a study relevant to the metabolism of benzene (1). The oxidation reactions produced acyclic dicarbonyl compounds The reactive 2,3-epoxyoxepin intermediates could neither be isolated nor observed spectroscopically [2], due, in part, to the acidic conditions of their generation. The present study makes a comparison between the oxidative metabolism of benzene through benzene oxide/oxepin with that of a “non-natural metabolite” of naphthalene: 4,5-benzoxepin. It is worthwhile to very briefly compare these metabolic pathways

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