Modeling the formation and reactions of benzene metabolites.
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 mono-oxygenase 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 (1)H 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.
Golding
Bernard T
BT
School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. b.t.golding@ncl.ac.uk
Barnes
Martine L
ML
Bleasdale
Christine
C
Henderson
Alistair P
AP
Jiang
Dong
D
Li
Xin
X
Mutlu
Esra
E
Petty
Hannah J
HJ
Sadeghi
Majid M
MM
D000447:Aldehydes / Q000378:metabolism; D001554:Benzene / Q000378:metabolism*; D003510:Cyclohexanes / Q000378:metabolism; D008954:Models, Biological; D010082:Oxepins / Q000378:metabolism; D010084:Oxidation-Reduction
D000447:Aldehydes; D003510:Cyclohexanes; D010082:Oxepins; C034476:muconaldehyde; D001554:Benzene; C023372:benzene oxide