The fate of benzene-oxide

Abstract

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.

Substrate interactions during the biodegradation of BTEX and THF mixtures by Pseudomonas oleovorans DT4

“…The strain Mycobacterium vaccae was claimed to yield hydroquinone as an end product by metabolizing benzene (Burback and Perry, 1993). In fact, hydroquinone was previously detected as the hepatic metabolite of benzene metabolism via cytochromes P450 in animal models (Shiga et al, 2010;Monks et al, 2010). Contrary to the previous reports so far, hydroquinone appeared as a transient intermediate in microbial benzene-degrading pathway, was further metabolized, and finally mineralized to CO 2 by a wide type microorganism (P. oleovorans DT4) (Fig.…”

Bacterial phenylalanine and phenylacetate catabolic pathway revealed

“…Cytochromes P450 are known to metabolize benzene to benzene-epoxide that equilibrates spontaneously with the oxepin. Further ring opening yields reactive aldehydes (36). Those compounds and also the spontaneous phenolic breakdown product of benzene-oxide are known to be reactive toward proteins and DNA and are potentially carcinogenic (37).…”

Biomonitoring Human Albumin Adducts: The Past, the Present, and the Future

“…169,170 These metabolites can react with blood proteins to form adducts (Figure 5, Table 1). 171,172 In the following, the studies of Alb-adducts found in vivo are summarized. Bechtold et al 97 found Alb-adducts of benzene formed with Cys34 in rats and humans.…”