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Chemical Compound Review

Benzeneoxide     7-oxabicyclo[4.1.0]hepta-2,4- diene

Synonyms: Benzene oxide, CHEMBL297630, CCRIS 2979, AG-D-94626, Arene oxide, ...
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Disease relevance of Dihydroepoxybenzene

  • Although many factors contribute to the outcome of pregnancies in epileptic women treated with phenytoin, a genetic defect in arene oxide detoxification seems to increase the risk of the baby having major birth defects [1].
  • The results provide the first evidence for a role of arene oxide drug metabolites in aplastic anemia in humans and suggest that enhanced susceptibility to toxicity may be based on an inherited abnormality in metabolite detoxification [2].
  • NIH shift in the hydroxylation of aromatic compounds by the ammonia-oxidizing bacterium Nitrosomonas europaea. Evidence against an arene oxide intermediate [3].
  • The reactive arene oxide may bind to macromolecules irreversibly and cause toxicity [4].
  • We present a case of the anticonvulsant hypersensitivity syndrome to emphasize the importance of recognizing the multiple clinical components of the syndrome and to raise awareness of the cross-sensitivity among anticonvulsants metabolized via arene oxide metabolites [5].

High impact information on Dihydroepoxybenzene

  • Benz[c]acridine (B[c]ACR) and 12 of its derivatives, including the 5 metabolically possible trans-dihydrodiols, the diastereomeric bay-region diol-epoxides, 2 non-bay-region diol-epoxides, and the K-region arene oxide, were tested for tumor-initiating activity on mouse skin [6].
  • Characterization of pulmonary arene oxide biotransformation using the perfused rabbit lung [7].
  • Experiments with 18O-enriched water showed that attack of water was exclusively at the allylic 2-position of the arene oxide, indicating that the 1R,2S-enantiomer of the oxide was preferentially hydrated by epoxide hydrolase [8].
  • This highly reactive intermediate attacks the aromatic ring at the C1 position and forms a radical sigma complex, which can either form an arene oxide or undergo a C1-C2 side-chain migration [9].
  • These drugs are thought to be activated to potentially reactive arene oxide (epoxide) metabolites by cytochrome P450-dependent monooxygenation, while liver microsomal epoxide hydrolase (mEH) plays a detoxifying role by converting such reactive intermediates to non-toxic dihydrodiols [10].

Chemical compound and disease context of Dihydroepoxybenzene


Biological context of Dihydroepoxybenzene

  • This behavior is coupled to an increase of the resistance to cell death and growth inhibition induced by benz(a)pyrene, whose activation proceeds through the NADPH-dependent arene oxide formation [13].

Anatomical context of Dihydroepoxybenzene

  • These data suggest that human microsomes metabolize this PCB through an arene oxide and that an "NIH shift" occurs [14].
  • Although both mice and rats showed dose-related increases in Hb and bone marrow protein adducts of BO and of the two benzoquinones, large intertissue and interspecies differences were noted, suggesting different preferences in metabolic pathways [15].
  • These results suggest that IMI is biotransformed into a chemically reactive metabolite (probably arene-oxide) through its 2-hydroxylation step by the CYP2D enzyme in rat liver microsomes, and the metabolite binds covalently to the enzyme itself, resulting in the inactivation [16].
  • Lamotrigine can be bioactivated to an arene oxide by rat hepatocytes in the absence of a major competing pathway such as N-glucuronidation [17].

Associations of Dihydroepoxybenzene with other chemical compounds

  • The enantioselectivity of native and purified hepatic microsomal epoxide hydrolase toward one symmetrical arene oxide, phenanthrene 9,10-oxide, and the resolved enantiomers of the three chiral arene oxide substrates, benzo[a]pyrene 4,5- and 7,8-oxide and benzo[a]anthracene 5,6-oxide was examined [18].
  • Hydroxylation proceeded primarily at the meta or para position either via an arene oxide, involving NIH shift and dechlorination, or by direct insertion of a hydroxyl group [19].
  • cis-Dihydrodiol, arene oxide and phenol metabolites of dictamnine: key intermediates in the biodegradation and biosynthesis of furoquinoline alkaloids [20].
  • We used adducts of hemoglobin (Hb) and bone marrow proteins to study the disposition of three benzene and metabolites (benzene oxide [BO], 1,2-benzoquinone [1,2-BQ], and 1,4-benzoquinone [1,4-BQ]) in F344 rats and B6C3F1 mice following a single oral dosage of [13C6]benzene and/or [14C]benzene [15].
  • Teratogenicity of the anticonvulsant drug phenytoin is thought to involve its bioactivation by cytochromes P-450 to a reactive arene oxide intermediate [21].

Gene context of Dihydroepoxybenzene


Analytical, diagnostic and therapeutic context of Dihydroepoxybenzene

  • Benzene oxide also coeluted with the HPLC peak of the previously unidentified metabolite [26].
  • A putative arene oxide intermediate (3H-AO), which was radiolabeled, was separated from 3H-TCB and BrAO by column chromatography, high pressure liquid chromatography (HPLC) and thin-layer chromatography (TLC), and was analyzed for TCBAO by methods that were independent of radiometric techniques [27].
  • Previous animal research has suggested that the phenytoin arene oxide metabolite is teratogenic in acute studies and that the fetal effects were increased after injecting an inhibitor of microsomal epoxide hydrolase (mEH) (Martz et al., Pharmacol Exp Ther 203:231-239, 1977, Barcellona et al., Teratog Carcinog Mutagen 7:159-168, 1987) [28].


  1. Genetic predisposition to phenytoin-induced birth defects. Strickler, S.M., Dansky, L.V., Miller, M.A., Seni, M.H., Andermann, E., Spielberg, S.P. Lancet (1985) [Pubmed]
  2. Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro. Gerson, W.T., Fine, D.G., Spielberg, S.P., Sensenbrenner, L.L. Blood (1983) [Pubmed]
  3. NIH shift in the hydroxylation of aromatic compounds by the ammonia-oxidizing bacterium Nitrosomonas europaea. Evidence against an arene oxide intermediate. Vannelli, T., Hooper, A.B. Biochemistry (1995) [Pubmed]
  4. Increased microsomal irreversible binding of phenytoin by valproic acid. Wang, S.L., Lai, M.L., Huang, J.D. Biochem. Pharmacol. (1991) [Pubmed]
  5. Cross-sensitivity and the anticonvulsant hypersensitivity syndrome. Moss, D.M., Rudis, M., Henderson, S.O. The Journal of emergency medicine. (1999) [Pubmed]
  6. Tumor-initiating activity of benz[c]acridine and twelve of its derivatives on mouse skin. Levin, W., Wood, A.W., Chang, R.L., Kumar, S., Yagi, H., Jerina, D.M., Lehr, R.E., Conney, A.H. Cancer Res. (1983) [Pubmed]
  7. Characterization of pulmonary arene oxide biotransformation using the perfused rabbit lung. Smith, B.R., Plummer, J.L., Ball, L.M., Bend, J.R. Cancer Res. (1980) [Pubmed]
  8. Differential stereoselectivity on metabolism of triphenylene by cytochromes P-450 in liver microsomes from 3-methylcholanthrene- and phenobarbital-treated rats. Thakker, D.R., Boehlert, C., Mirsadeghi, S., Levin, W., Ryan, D.E., Thomas, P.E., Yagi, H., Pannell, L.K., Sayer, J.M., Jerina, D.M. J. Biol. Chem. (1988) [Pubmed]
  9. 4-Hydroxyphenylpyruvate dioxygenase: a hybrid density functional study of the catalytic reaction mechanism. Borowski, T., Bassan, A., Siegbahn, P.E. Biochemistry (2004) [Pubmed]
  10. Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. Gaedigk, A., Spielberg, S.P., Grant, D.M. Pharmacogenetics (1994) [Pubmed]
  11. Pharmacokinetics of R-enantiomeric normephenytoin during chronic administration in epileptic patients. Bourgeois, B.F., Küpfer, A., Wad, N., Egli, M. Epilepsia (1986) [Pubmed]
  12. Relation of in vivo drug metabolism to stereoselective fetal hydantoin toxicology in mouse: evaluation of mephenytoin and its metabolite, nirvanol. Wells, P.G., Küpfer, A., Lawson, J.A., Harbison, R.D. J. Pharmacol. Exp. Ther. (1982) [Pubmed]
  13. Effect of glucose-6-phosphate dehydrogenase deficiency on the benz(a)pyrene toxicity for in vitro cultured human skin fibroblasts. Pirisi, L., Pascale, R., Daino, L., Frassetto, S., La Spina, V., Zanetti, S., Gaspa, L., Ledda, G.M., Garcea, R., Feo, F. Res. Commun. Chem. Pathol. Pharmacol. (1982) [Pubmed]
  14. The hydroxylation, dechlorination, and glucuronidation of 4,4'-dichlorobiphenyl (4-DCB) by human hepatic microsomes. Schnellmann, R.G., Volp, R.F., Putnam, C.W., Sipes, I.G. Biochem. Pharmacol. (1984) [Pubmed]
  15. The use of protein adducts to investigate the disposition of reactive metabolites of benzene. Rappaport, S.M., McDonald, T.A., Yeowell-O'Connell, K. Environ. Health Perspect. (1996) [Pubmed]
  16. Imipramine-induced inactivation of a cytochrome P450 2D enzyme in rat liver microsomes: in relation to covalent binding of its reactive intermediate. Masubuchi, Y., Igarashi, S., Suzuki, T., Horie, T., Narimatsu, S. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  17. Metabolism of lamotrigine to a reactive arene oxide intermediate. Maggs, J.L., Naisbitt, D.J., Tettey, J.N., Pirmohamed, M., Park, B.K. Chem. Res. Toxicol. (2000) [Pubmed]
  18. Enantioselectivity of microsomal epoxide hydrolase toward arene oxide substrates. Armstrong, R.N., Kedzierski, B., Levin, W., Jerina, D.M. J. Biol. Chem. (1981) [Pubmed]
  19. Hydroxylation and methylthiolation of mono-ortho-substituted polychlorinated biphenyls in rats: identification of metabolites with tissue affinity. Haraguchi, K., Kato, Y., Kimura, R., Masuda, Y. Chem. Res. Toxicol. (1998) [Pubmed]
  20. cis-Dihydrodiol, arene oxide and phenol metabolites of dictamnine: key intermediates in the biodegradation and biosynthesis of furoquinoline alkaloids. Boyd, D.R., Sharma, N.D., O'Dowd, C.R., Carroll, J.G., Loke, P.L., Allen, C.C. Chem. Commun. (Camb.) (2005) [Pubmed]
  21. Modulation of phenytoin teratogenicity and embryonic covalent binding by acetylsalicylic acid, caffeic acid, and alpha-phenyl-N-t-butylnitrone: implications for bioactivation by prostaglandin synthetase. Wells, P.G., Zubovits, J.T., Wong, S.T., Molinari, L.M., Ali, S. Toxicol. Appl. Pharmacol. (1989) [Pubmed]
  22. Human biotransformation of bropirimine. Characterization of the major bropirimine oxidative metabolites formed in vitro. Wynalda, M.A., Hauer, M.J., Wienkers, L.C. Drug Metab. Dispos. (1998) [Pubmed]
  23. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Pirmohamed, M., Kitteringham, N.R., Guenthner, T.M., Breckenridge, A.M., Park, B.K. Biochem. Pharmacol. (1992) [Pubmed]
  24. Purification and biochemical characterization of the rabbit pulmonary glutathione S-transferase: stereoselectivity and activity toward pyrene 4,5-oxide. Serabjit-Singh, C.J., Bend, J.R. Arch. Biochem. Biophys. (1988) [Pubmed]
  25. 2,2',5,5'-Tetrachlorobiphenyl: isolation and identification of metabolites generated by rat liver microsomes. Preston, B.D., Allen, J.R. Drug Metab. Dispos. (1980) [Pubmed]
  26. Identification of benzene oxide as a product of benzene metabolism by mouse, rat, and human liver microsomes. Lovern, M.R., Turner, M.J., Meyer, M., Kedderis, G.L., Bechtold, W.E., Schlosser, P.M. Carcinogenesis (1997) [Pubmed]
  27. Identification of an arene oxide metabolite of 2,2',5-5'-tetrachlorobiphenyl by gas chromatography-mass spectroscopy. Forgue, S.T., Allen, J.R. Chem. Biol. Interact. (1982) [Pubmed]
  28. Phenytoin embryopathy: effect of epoxide hydrolase inhibitor on phenytoin exposure in utero in C57BL/6J mice. Hartsfield, J.K., Holmes, L.B., Morel, J.G. Biochem. Mol. Med. (1995) [Pubmed]
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