Chemistry of muconaldehydes of possible relevance to the toxicology of benzene.

Bleasdale, Christine; Kennedy, Gordon T.; MacGregor, James O.; Nieschalk, Jens; Pearce, Kirsty; Watson, William P.; Golding, Bernard T.

doi:10.1289/ehp.961041201

Cited by 16 publications

(10 citation statements)

References 15 publications

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“…The mechanism of ring-opening remains debatable, but has been proposed to occur via cytochrome P450-mediated metabolism of the oxepin to the oxepinoxide [12] Further reduction or oxidation of MCA gives rise to a variety of products. In vitro model systems indicate that cytosolic aldehyde dehydrogenases may oxidize MCA to 6-oxo-trans-trans-hexadienoic acid, a mixed-aldehyde acid whose aldehyde functional group can undergo (i) oxidation to form trans-trans-muconic acid or (ii) reduction to 6-hydroxy-2,4- trans-trans-hexadienoic acid.…”

Section: Trans-trans-muconaldehyde (Mca)mentioning

confidence: 99%

The fate of benzene-oxide

Monks

Butterworth

Lau

2010

Chemico-Biological Interactions

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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 α-β-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. Coadministration 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 [3H]benzene are muconic acid, and glucuronide and/or sulfate conjugates of phenol, HQ, and catechol. Studies with [14C/13C]benzene revealed the presence in bone marrow of protein adducts of benzene oxide, 1,4-BQ, and 1,4-BQ, the relative abundance of which was both dose and species dependent. In particular, histones are bone marrow targets of [14C]benzene, although the identity of the reactive metabolite(s) giving rise to these adducts remain unknown. Finally, hematotoxic HQ-GSH conjugates are present in the bone marrow of rats receiving the HQ/phenol combination. In summary, although the fate of benzene oxide is known in remarkable detail, coupling this information to the site, and mechanism of action, remains to be established.

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Section: Trans-trans-muconaldehyde (Mca)mentioning

confidence: 99%

The fate of benzene-oxide

Monks

Butterworth

Lau

2010

Chemico-Biological Interactions

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“…The remaining benzene oxide is either hydrolyzed to produce catechol (CA) and 1,2-benzoquinone or reacts with glutathione to produce S -phenylmercapturic acid (SPMA). Metabolism of oxepin is thought to open the aromatic ring, yielding the reactive muconaldehydes and E,E -muconic acid (MA) [10]. Human exposures to benzene at air concentrations between 0.1 and 10 ppm, result in urinary metabolite profiles with 70–85% PH, 5–10% each of HQ, MA and CA, and less than 1% of SPMA [11] [12].…”

Section: Introductionmentioning

confidence: 99%

Human benzene metabolism following occupational and environmental exposures

Rappaport

Kim

Lan

et al. 2010

Chemico-Biological Interactions

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We previously reported evidence that humans metabolize benzene via two enzymes, including a hitherto unrecognized high-affinity enzyme that was responsible for an estimated 73 percent of total urinary metabolites [sum of phenol (PH), hydroquinone (HQ), catechol (CA), E,E-muconic acid (MA), and S-phenylmercapturic acid (SPMA)] in nonsmoking females exposed to benzene at sub-saturating (ppb) air concentrations. Here, we used the same Michaelis-Menten-like kinetic models to individually analyze urinary levels of PH, HQ, CA and MA from 263 nonsmoking Chinese women (179 benzene-exposed workers and 84 control workers) with estimated benzene air concentrations ranging from less than 0.001 ppm to 299 ppm. One model depicted benzene metabolism as a single enzymatic process (1-enzyme model) and the other as two enzymatic processes which competed for access to benzene (2-enzyme model). We evaluated model fits based upon the difference in values of Akaike’s Information Criterion (ΔAIC), and we gauged the weights of evidence favoring the two models based upon the associated Akaike weights and Evidence Ratios. For each metabolite, the 2-enzyme model provided a better fit than the 1-enzyme model with ΔAIC values decreasing in the order 9.511 for MA, 7.379 for PH, 1.417 for CA, and 0.193 for HQ. The corresponding weights of evidence favoring the 2-enzyme model (Evidence Ratios) were: 116.2:1 for MA, 40.0:1 for PH, 2.0:1 for CA and 1.1:1 for HQ. These results indicate that our earlier findings from models of total metabolites were driven largely by MA, representing the ring-opening pathway, and by PH, representing the ring-hydroxylation pathway. The predicted percentage of benzene metabolized by the putative high-affinity enzyme at an air concentration of 0.001 ppm was 88% based upon urinary MA and was 80% based upon urinary PH. As benzene concentrations increased, the respective percentages of benzene metabolized to MA and PH by the high-affinity enzyme decreased successively to 66% and 77% at 0.1 ppm, 20% and 58% at 1 ppm, and 2.7% and 17% at 10 ppm. This indicates that the putative high-affinity enzyme was active primarily below 1 ppm and favored the ring-opening pathway.

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“…(93) In DNA reacted with pBQ, the relative abundance was: pBQ-C ) pBQ-A ) pBQ-G. (94) The in vivo existence of these adducts has not yet been proved. Muconaldehyde also forms pyrrole ring-containing exocyclic adducts with purine nucleosides, (95) although their biochemical properties are unknown. Nevertheless, the formation of these adducts, if occurring in vivo, could contribute to benzene-related genotoxicity.…”

Section: Repair Of Six-membered Propano-g Derivatives and M 1 G By Thmentioning

confidence: 99%

Repair of exocyclic DNA adducts: rings of complexity

Hang

2004

BioEssays

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SummaryExocyclic DNA adducts are mutagenic lesions that can be formed by both exogenous and endogenous mutagens/ carcinogens. These adducts are structurally analogs but can differ in certain features such as ring size, conjugation, planarity and substitution. Although the information on the biological role of the repair activities for these adducts is largely unknown, considerable progress has been made on their reaction mechanisms, substrate specificities and kinetic properties that are affected by adduct structures. At least four different mechanisms appear to have evolved for the removal of specific exocyclic adducts. These include base excision repair, nucleotide excision repair, mismatch repair, and AP endonuclease-mediated repair. This overview highlights the recent progress in such areas with emphasis on structure-activity relationships. It is also apparent that more information is needed for a better understanding of the biological and structural implications of exocyclic adducts and their repair.

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Chemistry of muconaldehydes of possible relevance to the toxicology of benzene.

Cited by 16 publications

References 15 publications

The fate of benzene-oxide

The fate of benzene-oxide

Human benzene metabolism following occupational and environmental exposures

Repair of exocyclic DNA adducts: rings of complexity

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