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

Abstract

(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.

Tissue-Specific Metabolism of Benzene in Zymbal Gland and Other Solid Tumor Target Tissues in Rats

“…The ability of hydroquinone to deplete hepatic GSH levels is consistent with its oxidation to 1,4-benzoquinone and the direct reaction with glutathione to form an equivalent amount of 2-(S-glutathiony1)hydroquinone (Tunek et al, 1980;Lunte and Kissinger, 1983). Muconaldehyde has been reported recently to react with GSH to form several, as yet unidentified, metabolic products (Goon et al, 1993;Kline et al, 1993). The reactivity of muconaldehyde with glutathione is consistent with the a$-unsaturated aldehyde moieties present in the molecule (Kline et al, 1993).…”

“…Muconaldehyde has been reported recently to react with GSH to form several, as yet unidentified, metabolic products (Goon et al, 1993;Kline et al, 1993). The reactivity of muconaldehyde with glutathione is consistent with the a$-unsaturated aldehyde moieties present in the molecule (Kline et al, 1993). The ability of 1,2,4-benzenetriol to significantly decrease glutathione levels in liver homogenates may be related to its ease of oxidation to semiquinone or quinone intermediates (Lewis et al, 1988;Snyder, 1987) that can react with glutathione directly or deplete GSH via a free-radical mechanism (e.g., active oxygen species, oxidative stress) (Moldeus and Jernstrom, 1983;Ketterer, 1988;Ross, 1988).…”

The fate of benzene-oxide

“…It is important to note, however, that while [ 3 H]-trans-trans-muconic 14 acid and [ 14 C]-6-hydroxy-2,4-trans-trans-hexadienoic acid have been isolated from the urine, blood, and/or bone marrow of rodents treated with [ 3 H] or [ 14 C]benzene, the reactive aldehydes, MCA and 6-hydroxy-2,4-trans-trans-hexadienal, have yet to be isolated in vivo . Thus, while MCA is produced in liver microsomal incubations containing benzene [16], and is undoubtedly an in vivo metabolite of benzene, albeit transient, the reactivity of this metabolite (6 sec in the presence of GSH) suggests that hepatic-derived MCA is unlikely to reach the bone marrow in sufficient quantities to cause toxicity [17]. This again emphasizes the critical balance between the chemical stability and the biological reactivity of benzene metabolites with respect to their potential role in benzene-mediated hematotoxicity.…”

DNA-Protein Crosslink and DNA Strand Break Formation in HL-60 Cells Treated with Trans, trans-Muconaldehyde, Hydroquinone and Their Mixtures

“…At present, the chemical nature of DNAPC induced by MUC is not known. Muconaldehyde is a multifunctional electrophilic compound that has been shown in vitro to react with proteins (Udupi, Goldstein, and Witz 1994), thiols (Kline et al 1993;Goon, Matsuura, and Ross 1993), DNA (Latriano et al 1989), and deoxyguanosine (Schatz-Kornburst, Goldstein, and Witz 1991). Our previous studies on structureactivity relationships showed that the aldehyde groups and the ®,¯-unsaturated double bond system are important structural features in DNAPC induction by MUC (Schoenfeld and Witz 2000).…”