Muconaldehyde, A Potential Toxic Intermediate of Benzene Metabolism

Goldstein, Bernard D.; Witz, Gisela; Javid, Jamshid; Amoruso, Marie A.; Rossman, Toby G.; Wolder, Bonnie

doi:10.1007/978-1-4757-0674-1_20

Cited by 54 publications

(31 citation statements)

References 6 publications

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“…Although the exact chemical nature of the ultimate toxic or carcinogenic species remains unknown, several metabolic pathways proposed for benzene lead to the formation of reactive intermediates. Of importance are those pathways giving rise to mono-and polyhydroxylated metabolites (e.g., phenol, hydroquinone, catechol, 1,2,4-benzenetriol), ring-opened metabolites (e.g., muconaldehyde, muconic acid) and biphenolic metabolites (e.g., 4,4'-biphenol) (9)(10)(11)(12)(13)(14)(15). The metabolism of benzene has been extensively studied in the liver and bone marrow (4,(19)(20)(21), but little effort has been than 99%.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Metabolism of Benzene in Zymbal Gland and Other Key Target Tissues after Oral Administration in Rats

Low¹,

Meeks²,

Norris³

et al. 1989

Environmental Health Perspectives

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Solid tumors have been reported in the Zymbal gland, oral and nasal cavities, and mammary gland of Sprague-Dawley rats following chronic oral administration of benzene. The cause for the specificity of such lesions remains unclear, but it is possible that tissue-specific metabolism or pharmacokinetics of benzene is responsible. Metabolism and pharmacokinetic studies were carried out in our laboratory with '4C-benzene at oral doses of 0.15 to 500 mg/kg to ascertain tissue retention, metabolite profile, and elimination kinetics in target and nontarget organs and in blood. Findings from thoses studies indicate the following: a) the Zymbal gland is not a sink or a site of accumulation for benzene or its metabolites even after a single high dose (500 mg/kg) or after repeated oral administration; b) the metabolite profile is quantitatively different in target tissues (e.g., Zymbal gland, nasal cavity), nontarget tissues and blood; and c) pharmacokinetic studies show that the elimination of radioactivity from the Zymbal gland is biphasic.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Metabolism of Benzene in Zymbal Gland and Other Key Target Tissues after Oral Administration in Rats

Low¹,

Meeks²,

Norris³

et al. 1989

Environmental Health Perspectives

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show abstract

“…Introduction trans,trans-Muconaldehyde (TTM), an a,3-unsaturated diene dialdehyde, has been suggested by Goldstein et al (1) to be a toxic intermediate in the metabolism of benzene to trans,trans-muconic acid. Since the early studies of Parke and Williams it has been known that benzene is metabolized to this ring-opened dicarboxcylic acid (2).…”

mentioning

confidence: 99%

Chromatographic and spectrophotometric characterization of adducts formed during the reaction of trans,trans-muconaldehyde with 14C-deoxyguanosine 5'-phosphate.

Latriano

Witz

Goldstein

et al. 1989

Environ Health Perspect

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Mice liver microsomes oxidatively open the benzene ring to form trans,trans-muconaldehyde, a hematotoxic unsaturated aldehyde. In the present studies, 4.5 imole trans,trans-muconaldehyde was reacted with "4C-2'deoxyguanosine 5'-phosphate in phosphate buffer. Products were separated by high performance liquid chromatography (HPLC). Absorbance was monitored using a diode array detector, and aliquots of the HPLC eluant were collected for UV spectrophotometric analysis and scintillation counting. Under these conditions, deoxyguanosine 5'-phosphate eluted at 12.5 min and muconaldehyde at 22.0 min. The HPLC and radioactivity profiles of the muconaldehyde/deoxyguanosine reaction mixture indicated the presence of multiple adducts. Three adducts were detected eluting at 36, 39, and 42 min, which represented approximately 2.5, 2.5, and 1% of the radioactivity, respectively. These adducts had similar UV spectra with absorption maxima between 334 and 347 nm. Another product of the reaction mixture, eluting at 19.0 min and accounting for 10% of the radioactivity, was also observed. This compound had absorption maxima at 348 and 372 nm. These results suggest that trans,trans-muconaldehyde can react with deoxyguanosine monophosphate in vitro under physiological conditions to form stable adducts. Studies are being conducted to determine the structure of these adducts and whether these adducts are formed by the reaction of DNA with muconaldehyde or metabolically activated benzene.

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“…Two questions are raised immediately by this scheme: Any peroxidase enzyme is likely to be able to catalyze the conversion of hydroquinone to 1,4-benzoquinone, so why is MPO shown as the sole activating enzyme? What role, if any, does another putative toxic metabolite of benzene, i.e., trans,trans-muconaldehyde (25,26), play since it is omitted from this scheme? Clearly some caveats must be placed on the proposed scheme.…”

Section: Peroxidase-dependent Metabolism Of Hydroquinone and The Stimmentioning

confidence: 99%

“…It may also be important for benzene's myelotoxic effects, but does not rule out a role for another putative toxic metabolite of benzene, i.e., trans,trans-muconaldehyde (25,26). Table 2.…”

Section: Metabolites Of Benzenementioning

confidence: 99%

Peroxidase-Dependent Metabolism of Benzene's Phenolic Metabolites and Its Potential Role in Benzene Toxicity and Carcinogenicity

Smith¹,

Yager²,

Steinmetz³

et al. 1989

Environmental Health Perspectives

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Muconaldehyde, A Potential Toxic Intermediate of Benzene Metabolism

Cited by 54 publications

References 6 publications

Pharmacokinetics and Metabolism of Benzene in Zymbal Gland and Other Key Target Tissues after Oral Administration in Rats

Pharmacokinetics and Metabolism of Benzene in Zymbal Gland and Other Key Target Tissues after Oral Administration in Rats

Chromatographic and spectrophotometric characterization of adducts formed during the reaction of trans,trans-muconaldehyde with 14C-deoxyguanosine 5'-phosphate.

Peroxidase-Dependent Metabolism of Benzene's Phenolic Metabolites and Its Potential Role in Benzene Toxicity and Carcinogenicity

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