Reaction of (E,E)-muconaldehyde and its aldehydic metabolites, (E,E)-6-oxohexadienoic acid and (E,E)-6-hydroxyhexa-2,4-dienal, with glutathione.

(E,E)-Muconaldehyde (muconaldehyde) has been identified as a hematotoxic metabolite of benzene in vitro. It is metabolized in mouse liver cytosol to oxidized and reduced derivatives including the alpha, beta-unsaturated aldehydes (E,E)-6-oxohexadienoic acid and (E,E)-6-hydroxy-2,4-hexadienal. In this study we have synthesized the aldehydic metabolites of muconaldehyde. The reaction of glutathione with muconaldehyde and its aldehyde metabolites was investigated. Reactions were bimolecular and stoichiometric in aldehyde and glutathione in the initial phases. Second-order rate constants were determined, and the rates were in the order muconaldehyde > (E,E)-6-hydroxy-2,4-hexadienal > (E,E)-6-oxohexadienoic acid. Further investigation of the reaction of muconaldehyde with glutathione showed that the bimolecular reaction is reversible but the initial product decomposed irreversibly to two or more products, one of which had a red-shifted UV spectrum. Rate constants for these subsequent reactions were determined. The results are discussed in terms of the toxicity of muconaldehyde at tissues distal from the liver, where it is believed to be formed from the metabolism of benzene.