Identification of 6-hydroxy-trans,trans-2,4-hexadienoic acid, a novel ring-opened urinary metabolite of benzene.

Kline, Stanley A.; Robertson, Jamie; Grotz, V. Lee; Goldstein, Bernard D.; Witz, Gisela

doi:10.1289/ehp.93101310

Cited by 10 publications

(3 citation statements)

References 12 publications

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“…However, at that time the prevailing view was that the cis-cis isomer was the primary product, and it was not until 1952 that Parke and Williams unequivocally confirmed the structure as trans-trans-muconic acid, following [ 14 C]-benzene administration to rabbits [14]). Alternatively, cytosolic alcohol dehydrogenases can reduce (reversible reaction) MCA to 6-hydroxy-2,4-trans-trans-hexadienal, a mixed-aldehyde alcohol whose aldehyde functional group can undergo oxidation to form 6-hydroxy-2,4-3 trans-trans-hexadienoic acid [15]. 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 .…”

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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“…Further studies on the metabolism of muconaldehyde described metabolic pathways involving alcohol dehydrogenase and aldehyde dehydrogenase in which muconaldehyde was converted to a di-alcohol, an alcohol-aldehyde, an acidaldehyde and an alcohol-acid. [52][53][54] Indeed, Kline et al 55 identified 6-OH-trans, trans-2, 4-hexadienoic acid in the urine of benzene-treated mice. Zhang et al 53 demonstrated that all of the steps in the metabolism of trans, trans-muconaldehyde are irreversible except the interconversion of the aldehyde, alcohol with the parent compound aldehyde, aldehyde (muconaldehyde).…”

Section: Role Of Ring Openingmentioning

confidence: 99%

Benzene's toxicity: a consolidated short review of human and animal studies by HA Khan

Snyder

2007

Hum Exp Toxicol

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Khan's review is a brief summary of the complex field of study revolving around bone marrow toxicity and leukemogenesis observed in people chronically exposed to benzene. These comments are intended to demonstrate the use of the Kahn review as a launching pad for an in-depth analysis of the several related areas that must be fully explored to understand benzene-related diseases. The accumulated evidence demonstrates that benzene-induced bone marrow damage results from the production of hematotoxins that are metabolic products of benzene metabolism. The metabolism of benzene is described with respect to the formation benzene metabolites with emphasis on phenol and hydroquinone, which are the major metabolites, the significance of the formation of glutathione conjugates, the activity of NAD(P)H:quinone oxidoreductase (NQO1), and the ring opening products. Results are shown suggesting that oxidative stress induced by benzene metabolites is likely to be a significant factor in damaging DNA in bone marrow cells. Although a variety of effects on bone marrow can be demonstrated it is not yet clear which metabolites are most important in either benzene-induced aplastic anemia or leukemia. Benzene metabolism alone is insufficient to fully describe benzene toxicity. The impact of benzene metabolites on bone marrow cells must be fully explored to determine how benzene exposure can result in decreased viability or genetic toxicity to cells in the bone marrow. Human & Experimental Toxicology (2007) 26, 687— 696

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“…In addition to L-phenylmercapturic acid reported by Parke and Williams (1), other mercapturates include 6-N-acetylcysteinyl-S-2,3-cyclohexadienol (14,15) and 2,5-diOH-phenylmercapturic acid (16). The urine also contains two ring-opening products, i.e., trans-trans-muconic acid (1,17) and 6-OH-t,t-2,4-hexadienoic acid (18), and the residue of a covalently bound DNA adduct, i.e., N7-phenylguanine (19,20).…”

Section: Urinary Metabolitesmentioning

confidence: 99%

An overview of benzene metabolism.

Snyder

Hedli

1996

Environ Health Perspect

261

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Benzene toxicity involves both bone marrow depression and leukemogenesis caused by damage to multiple classes of hematopoietic cells and a variety of hematopoietic cell functions. Study of the relationship between the metabolism and toxicity of benzene indicates that several metabolites of benzene play significant roles in generating benzene toxicity. Benzene is metabolized, primarily in the liver, to a variety of hydroxylated and ring-opened products that are transported to the bone marrow where subsequent secondary metabolism occurs. Two potential mechanisms by which benzene metabolites may damage cellular macromolecules to induce toxicity include the covalent binding of reactive metabolites of benzene and the capacity of benzene metabolites to induce oxidative damage. Although the relative contributions of each of these mechanisms to toxicity remains unestablished, it is clear that different mechanisms contribute to the toxicities associated with different metabolites. As a corollary, it is unlikely that benzene toxicity can be described as the result of the interaction of a single metabolite with a single biological target. Continued investigation of the metabolism of benzene and its metabolites will allow us to determine the specific combination of metabolites as well as the biological target(s) involved in toxicity and will ultimately lead to our understanding of the relationship between the production of benzene metabolites and bone marrow toxicity.

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Identification of 6-hydroxy-trans,trans-2,4-hexadienoic acid, a novel ring-opened urinary metabolite of benzene.

Cited by 10 publications

References 12 publications

The fate of benzene-oxide

The fate of benzene-oxide

Benzene's toxicity: a consolidated short review of human and animal studies by HA Khan

An overview of benzene metabolism.

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