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Modeling the formation and reactions of benzene metabolites

Lookup NU author(s): Emeritus Professor Bernard Golding, Martine Barnes, Dr Christine Bleasdale, Dr Alistair Henderson, Dong Jiang, Esra Mutlu, Professor Majid Sadeghi

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Abstract

One or more of the muconaldehyde isomers is a putative product of benzene metabolism. As muconaldehydes are highly reactive dienals and potentially mutagenic they might be relevant to the carcinogenicity of benzene. Muconaldehydes may be derived through the action of a cytochrome P450 monooxygenase on benzene oxide-oxepin, which are established metabolites of benzene. Oxidation of benzene oxide-oxepin either by the one-electron oxidant cerium(IV) ammonium nitrate (CAN) or by iron(III) tris(1,10-phenanthroline) hexafluorophosphate in acetone at -78 degrees C or acetonitrile at -40 degrees C gave (E,Z)-muconaldehyde, which was a single diastereoisomer according to analysis by H-1 NMR spectroscopy. Reaction of toluene-1,2-oxide/2-methyloxepin with CAN gave (2E,4Z)-6-oxo-hepta-2,4-dienal. Similarly, the action of CAN on 1,6-dimethylbenzene oxide-2,7-dimethyloxepin gave (3Z,5E)-octa-3,5-diene-2,7-dione. In vivo, benzene oxide-oxepin could suffer one-electron oxidation by cytochrome P450 mono-oxygenase giving (E,Z)-muconaldehyde. The observations presented may be relevant to the toxicology of benzene oxide-oxepin and other arene oxide-oxepins as we have previously shown that (E,Z)-muconaldehyde, analogously to (Z,Z)-muconaldehyde, affords pyrrole adducts with the exocyclic amino groups of the DNA bases adenine and guanine. Independent of their possible toxicological significance, the experiments described provide preparatively useful routes to (E,Z)-muconaldehyde and its congeners. Methods are also described for the trapping and analysis of reactive benzene metabolites, e.g. using the Diels-Alder reaction with the dienophile 4-phenyl-1,2,4-triazoline-3,5-dione to trap arene oxides and with the diene 1,3-diphenylisobenzofuran to trap enals. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Publication metadata

Author(s): Golding BT, Barnes ML, Bleasdale C, Henderson AP, Jiang D, Li X, Mutlu E, Petty HJ, Sadeghi MM

Publication type: Article

Publication status: Published

Journal: Chemico-Biological Interactions

Year: 2010

Volume: 184

Issue: 1-2

Pages: 196-200

Print publication date: 11/01/2010

ISSN (print): 0009-2797

ISSN (electronic): 1872-7786

Publisher: Elsevier Ireland Ltd

URL: http://dx.doi.org/10.1016/j.cbi.2010.01.001

DOI: 10.1016/j.cbi.2010.01.001

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