muconaldehyde and benzene-oxide

Metabolism is a prerequisite for the development of benzene-mediated myelotoxicity. Benzene is initially metabolized via cytochromes P450 (primarily CYP2E1 in liver) to benzene-oxide, which subsequently gives rise to a number of secondary products. Benzene-oxide equilibrates spontaneously with the corresponding oxepine valence tautomer, which can ring open to yield a reactive alpha,beta-unsaturated aldehyde, trans-trans-muconaldehyde (MCA). Further reduction or oxidation of MCA gives rise to either 6-hydroxy-trans-trans-2,4-hexadienal or 6-hydroxy-trans-trans-2,4-hexadienoic acid. Both MCA and the hexadienal metabolite are myelotoxic in animal models. Alternatively, benzene-oxide can undergo conjugation with glutathione (GSH), resulting in the eventual formation and urinary excretion of S-phenylmercapturic acid. Benzene-oxide is also a substrate for epoxide hydrolase, which catalyzes the formation of benzene dihydrodiol, itself a substrate for dihydrodiol dehydrogenase, producing catechol. Finally, benzene-oxide spontaneously rearranges to phenol, which subsequently undergoes either conjugation (glucuronic acid or sulfate) or oxidation. The latter reaction, catalyzed by cytochromes P450, gives rise to hydroquinone (HQ) and 1,2,4-benzene triol. Co-administration of phenol and HQ reproduces the myelotoxic effects of benzene in animal models. The two diphenolic metabolites of benzene, catechol and HQ undergo further oxidation to the corresponding ortho-(1,2-), or para-(1,4-)benzoquinones (BQ), respectively. Trapping of 1,4-BQ with GSH gives rise to a variety of HQ-GSH conjugates, several of which are hematotoxic when administered to rats. Thus, benzene-oxide gives rise to a cascade of metabolites that exhibit biological reactivity, and that provide a plausible metabolic basis for benzene-mediated myelotoxicity. Benzene-oxide itself is remarkably stable, and certainly capable of translocating from its primary site of formation in the liver to the bone marrow. However, therein lies the challenge, for although there exists a plethora of information on the metabolism of benzene, and the fate of benzene-oxide, there is a paucity of data on the presence, concentration, and persistence of benzene metabolites in bone marrow. The major metabolites in bone marrow of mice exposed to 50 ppm [(3)H]benzene are muconic acid, and glucuronide and/or sulfate conjugates of phenol, HQ, and catechol. Studies with [(14)C/(13)C]benzene revealed the presence in bone marrow of prote

Topics: Aldehydes; Animals; Benzene; Bone Marrow; Cyclohexanes; Glutathione; Hydroquinones; Mice; Phenol; Rats

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.

Topics: Aldehydes; Benzene; Cyclohexanes; Models, Biological; Oxepins; Oxidation-Reduction

Oxidation of 7-oxabicyclo[4.1.0]hepta-2,4-diene (benzene oxide)/oxepin with dimethyldioxirane (DMDO) gave mainly (Z,Z)-muconaldehyde, with complete diastereoselectivity. Similarly, 2-methyl-7-oxabicyclo[4.1.0]hepta-2,4-diene (toluene 1,2-epoxide)/2-methyloxepin gave (Z,Z)-1,6-dioxohepta-2,4-diene, while 2,6-dimethyl-7-oxabicyclo[4.1.0]hepta-2,4-diene (1,2-dimethylbenzene 1,2-epoxide)/2,7-dimethyloxepin gave (Z,Z)-2,7-dioxo-3,5-octadiene. By monitoring the DMDO oxidation of benzene oxide/oxepin by 1H NMR spectroscopy, a significant byproduct was identified as 4,8-dioxabicyclo[5.1.0]octa-2,5-diene (sym-oxepin oxide). This observation supports the hypothesis that the route to (Z,Z)-muconaldehyde proceeds from oxepin via 6,8-dioxabicyclo[5.1.0]octa-2,4-diene (oxepin 2,3-oxide), with a minor pathway leading to sym-oxepin oxide. The DMDO oxidations described provide model systems for the cytochrome P450-dependent metabolism of benzene and for the atmospheric photooxidation of benzenoid hydrocarbons.

Topics: Aldehydes; Animals; Benzene; Cyclohexanes; Epoxy Compounds; Magnetic Resonance Spectroscopy; Mice; Microsomes, Liver; Models, Chemical; Oxepins; Oxidation-Reduction; Photochemistry