Energetics of the metabolic production of (E,E)-muconaldehdye from benzene via the intermediates 2,3-epoxyoxepin and (Z,Z)- and (E,Z)-muconaldehyde: Ab initio molecular orbital calculations

Greenberg, Arthur; Bock, Charles W.; George, Philip; Glusker, Jenny P.

doi:10.1021/tx00035a016

Cited by 16 publications

(12 citation statements)

References 38 publications

(62 reference statements)

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“…In the first step, oxepin undergoes enzymatic epoxidation of oxepin (7 in fig 4), an equilibrium product of benzene oxide, to transoid-2,3-epoxyoxepin (8 in fig 4). 27 This intermediate spontaneously rearranges to muconaldehye, and would have a short half life in biological systems (<1 minute). Oxepin would be expected to compete for the same active site in the cytochrome as does benzene and phenol.…”

Section: Discussionmentioning

confidence: 99%

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

Rothman¹,

Bechtold²,

Yin³

et al. 1998

Occup Environ Med

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Objectives-Animal inhalation studies and theoretical models suggest that the pattern of formation of benzene metabolites changes as exposure to benzene increases. To determine if this occurs in humans, benzene metabolites in urine samples collected as part of a cross sectional study of occupationally exposed workers in Shanghai, China were measured. Methods-With organic vapour monitoring badges, 38 subjects were monitored during their full workshift for inhalation exposure to benzene. The benzene urinary metabolites phenol, catechol, hydroquinone, and muconic acid were measured with an isotope dilution gas chromatography mass spectroscopy assay and strongly correlated with concentrations of benzene air. For the subgroup of workers (n=27) with urinary phenol >50 ng/g creatinine (above which phenol is considered to be a specific indicator of exposure to benzene), concentrations of each of the four metabolites were calculated as a ratio of the sum of the concentrations of all four metabolites (total metabolites) and were compared in workers exposed to >25 ppm v < 25 ppm. Results-The median, 8 hour time weighted average exposure to benzene was 25 ppm. Relative to the lower exposed workers, the ratio of phenol and catechol to total metabolites increased by 6.0% (p=0.04) and 22.2% (p=0.007), respectively, in the more highly exposed workers. By contrast, the ratio of hydroquinone and muconic acid to total metabolites decreased by 18.8% (p=0.04) and 26.7% (p=0.006), respectively. Similar patterns were found when metabolite ratios were analysed as a function of internal benzene dose (defined as total urinary benzene metabolites), although catechol showed a more complex, quadratic relation with increasing dose. Conclusions-These results, which are consistent with previous animal studies, show that the relative production of benzene metabolites is a function of exposure level. If the toxic benzene metabolites are assumed to be derived from hydroquinone, ring opened products, or both, these results suggests that the risk for adverse health outcomes due to exposure to benzene may have a supralinear relation with external dose, and that linear extrapolation of the toxic eVects of benzene in highly exposed workers to lower levels of exposure may underestimate risk. (Occup Environ Med 1998;55:705-711)

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Section: Discussionmentioning

confidence: 99%

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

Rothman¹,

Bechtold²,

Yin³

et al. 1998

Occup Environ Med

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“…4.109 [2] [5]), leading to S-phenylmercapturic acid (5.119), a urinary biomarker for benzene exposure [196]. This product is further metabolized by epoxidation and ring opening to yield (Z,Z)-muconaldehyde ((Z,Z)-121), followed by isomerization to (E,E)-muconaldehyde ((E,E)-121); both dialdehydes were hepatotoxic when injected to mice and react readily with glutathione (not shown) [198]. 3.68 [2] [4]) to yield 1,2-dihydrobenzene-1,2-diol (5.123).…”

Section: Fig 548mentioning

confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Testa

Kraemer

2009

ChemInform

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The Part 5 of our biochemical introduction to drug metabolism presents the pharmacological and toxicological consequences of drug and xenobiotic metabolism. As we have already shown [1 -5] and discuss here with specific focus, the consequences of the biotransformation of foreign compounds explain to a large extent the immense significance this discipline has acquired. When it comes to drug metabolism, its consequences are of utmost relevance in fields such as drug discovery and development, clinical pharmacology and toxicology, and therapeutics. The same relevance is now recognized to xenobiotic metabolism in, e.g., agrochemistry and food chemistry, industrial hygiene, workplace safety, and environmental welfare.Presenting the pharmacological and toxicological consequences of drug and xenobiotic metabolism can be achieved by focusing on rules and general principles, with a high risk of remaining abstract and failing to impress readers. Or it can be done with examples only, with the consequence that readers will remember fragmental data which may not help them to generalize and reason by analogy. The didactic approach followed here is simply the middle course, whereby we start with principles and illustrate them with examples, while, at other occasions, discussing illustrative cases from which principles are then derived.

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“…(1) Geometry. Previous calculations established the existence of a stable axial and a stable equatorial form of 2-formyl-2/i-pyran in which the formyl group is situated, respectively, below the nominal pyran ring plane and in the nominal ring plane (11). Further calculations have now identified another stable axial and another stable equatorial form.…”

Section: Resultsmentioning

confidence: 91%

“…The presence in urine of one of its metabolic oxidation products, (£,E)-muconic acid, i.e., HOOCCH=CHCH=CHCOOH with the double bonds in the trans (E) configuration, is widely used as an indicator of benzene exposure (5). The pathway by which this is formed is of considerable interest because it can evidently compete successfully with the other reaction pathways by which benzene is converted into phenol, the dihydrol, or In broad outline, ab initio molecular orbital calculations at the MP2/6-31 G*//RHF/6-31G* level which we have reported in a recent publication (11) support the above reaction pathway. Model reactions simulating the microsomal monooxygenase system show the formation of benzene oxide and the epoxyoxepin to be very favorable exothermic processes.…”

Section: Introductionmentioning

confidence: 98%

An ab Initio Computational Molecular Orbital Study of the Conformers of Muconaldehyde, and the Possible Role of 2-Formyl-2H-pyran in Bringing about the Conversion of a(Z,Z)-Muconaldehyde Structure to an (E,Z)-Muconaldehyde Structure

Bock¹,

George²,

Greenberg³

et al. 1994

Chem. Res. Toxicol.

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To determine whether conformers of 2-formyl-2H-pyran (2F2HP) can serve as intermediates in the isomerization (Z,Z)-muconaldehyde-->(E,Z)-muconaldehyde--an essential step in the metabolic oxidation of benzene in which (E,E)-muconic acid is formed--we have carried out ab initio molecular orbital calculations at the MP2/6-31G* (frozen core, valence orbitals active) level with full geometry optimization at the RHF/6-31G* level. Taking account of the configuration about the carbon-carbon single bonds as well as that about the double bonds, the six conformers of (Z,Z)-muconaldehyde have been characterized, as well as the eight conformers of (E,Z)-muconaldehyde. Axial and equatorial conformers of 2F2HP have been identified, which exist in stable syn or anti forms depending on the relative position of the pyran and carbonyl O-atoms. Each step in the metabolic pathway is stereospecific. The initial ring opening in 2,3-epoxyoxepin gives (eZzZz)-muconaldehyde, which then undergoes ring closure to give anti-axial-2F2HP (step a). Inversion of the ring gives anti-equatorial-2F2HP, which upon ring opening gives (zEzZz)-muconaldehyde (step b). An alternative pathway links (zZzZz)-muconaldehyde with syn-axial-2F2HP (step a'), and syn-equatorial with (eEzZz)-muconaldehyde (step b'). Half-reaction times, taking into account the fractional representation of each reacting conformer in rapidly established equilibrium mixtures, suggest that the operative pathway is via step a, with little to choose between steps b and b'.

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Energetics of the metabolic production of (E,E)-muconaldehdye from benzene via the intermediates 2,3-epoxyoxepin and (Z,Z)- and (E,Z)-muconaldehyde: Ab initio molecular orbital calculations

Cited by 16 publications

References 38 publications

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

Urinary excretion of phenol, catechol, hydroquinone, and muconic acid by workers occupationally exposed to benzene.

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

An ab Initio Computational Molecular Orbital Study of the Conformers of Muconaldehyde, and the Possible Role of 2-Formyl-2H-pyran in Bringing about the Conversion of a(Z,Z)-Muconaldehyde Structure to an (E,Z)-Muconaldehyde Structure

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