Structure-activity relationships in the mutagenicity and cytotoxicity of putative metabolites and related analogs of benzene derived from the valence tautomers benzene oxide and oxepin

Stark, Avishay‐Abraham; Rastetter, William H.

doi:10.1002/(sici)1098-2280(1996)28:3<284::aid-em13>3.0.co;2-b

Cited by 9 publications

(10 citation statements)

References 42 publications

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“…It is interesting to consider the selectivity toward the double bonds of oxepin by cytochrome P450 monooxygenase. This raises the question as to whether sym -oxepin oxide ( 3b ) is a bona fide metabolite of benzene, and if so, what are the toxicological consequences (see ref for a discussion of this issue). The results described also provide a model for the conversion of benzene into muconaldehydes under conditions of photooxidation.…”

Section: Discussionmentioning

confidence: 99%

“…1,2-Dimethylbenzene 1,2-Epoxide/2,7-Dimethyloxepin (1e/1f). This compound was prepared essentially as described (17) (5), 91 (9), 77 (32), 65 (7), 59 (18), 43 (100), 32 (16).…”

Section: -Methyl-45-dibromocyclohexene 12-epoxidementioning

confidence: 99%

“…(Z,Z)-Muconaldehyde (2a). This was obtained as a yellow solid (80 mg, 64%), which was purified by dissolution in the minimum amount of diethyl ether followed by the addition of cold petroleum ether: υmax (in KBr) 1663 cm -1 ; 1 H NMR (200 MHz, CDCl3) δ 10.40 (2H, d, J ) 7.0 Hz, 1-H, 6-H), 8.16 (2H, dd, J ) 2.6, 7.6 Hz, 3-H, 4-H), 6.25 (2H, m, 2-H, 5-H); MS (EI) 110 (M + , 70), 88 (13), 81 ([M -CHO] + , 100), 57 (32), 53 (72), 44 (16), 32 (27) [data identical with that from an authentic sample (13)].…”

Section: -Methyl-45-dibromocyclohexene 12-epoxidementioning

confidence: 99%

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Dimethyldioxirane Converts Benzene Oxide/Oxepin into (Z,Z)-Muconaldehyde and sym-Oxepin Oxide: Modeling the Metabolism of Benzene and Its Photooxidative Degradation

Bleasdale

Cameron

Edwards

et al. 1997

Chem. Res. Toxicol.

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Oxidation of 7-oxabicyclo[4.1.0]hepta-2,4-diene (benzene oxide)/oxepin with dimethyldioxirane (DMDO) gave mainly (Z,Z)-muconaldehyde, with complete diastereoselectivity. Similarly, 2-methyl-7-oxabicyclo[4.1.0]hepta-2,4-diene (toluene 1,2-epoxide)/2-methyloxepin gave (Z,Z)-1,6-dioxohepta-2,4-diene, while 2,6-dimethyl-7-oxabicyclo[4.1.0]hepta-2,4-diene (1,2-dimethylbenzene 1,2-epoxide)/2,7-dimethyloxepin gave (Z,Z)-2,7-dioxo-3,5-octadiene. By monitoring the DMDO oxidation of benzene oxide/oxepin by 1H NMR spectroscopy, a significant byproduct was identified as 4,8-dioxabicyclo[5.1.0]octa-2,5-diene (sym-oxepin oxide). This observation supports the hypothesis that the route to (Z,Z)-muconaldehyde proceeds from oxepin via 6,8-dioxabicyclo[5.1.0]octa-2,4-diene (oxepin 2,3-oxide), with a minor pathway leading to sym-oxepin oxide. The DMDO oxidations described provide model systems for the cytochrome P450-dependent metabolism of benzene and for the atmospheric photooxidation of benzenoid hydrocarbons.

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Section: Discussionmentioning

confidence: 99%

“…1,2-Dimethylbenzene 1,2-Epoxide/2,7-Dimethyloxepin (1e/1f). This compound was prepared essentially as described (17) (5), 91 (9), 77 (32), 65 (7), 59 (18), 43 (100), 32 (16).…”

Section: -Methyl-45-dibromocyclohexene 12-epoxidementioning

confidence: 99%

Section: -Methyl-45-dibromocyclohexene 12-epoxidementioning

confidence: 99%

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Dimethyldioxirane Converts Benzene Oxide/Oxepin into (Z,Z)-Muconaldehyde and sym-Oxepin Oxide: Modeling the Metabolism of Benzene and Its Photooxidative Degradation

Bleasdale

Cameron

Edwards

et al. 1997

Chem. Res. Toxicol.

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“…Furthermore, putative adducts of BO with proteins [i.e., S- phenylcysteine from hemoglobin (Hb) and albumin (Alb)] ( − ) and with DNA () have been detected in animals and workers exposed to large amounts of benzene. And while there is some conflicting evidence concerning BO's mutagenicity (), at least two separate groups have reported that BO is mutagenic in the Ames bioassay ( , ).…”

Section: Introductionmentioning

confidence: 99%

Formation of Hemoglobin and Albumin Adducts of Benzene Oxide in Mouse, Rat, and Human Blood

Lindstrom

Yeowell-O'Connell

Waidyanatha

et al. 1998

Chem. Res. Toxicol.

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Little is known about the formation and disposition of benzene oxide (BO), the initial metabolite arising from oxidation of benzene by cytochrome P450. In this study, reactions of BO with hemoglobin (Hb) and albumin (Alb) were investigated in blood from B6C3F1 mice, F344 rats, and humans in vitro. The estimated half-lives of BO in blood were 6.6 min (mice), 7.9 min (rats), and 7.2 min (humans). The following second-order rate constants were estimated for reactions between BO and cysteinyl residues of Hb and Alb [in units of L (g of Hb- or Alb-h)-1]: mouse Hb = 1.16 x 10(-)4, rat Hb = 15.4 x 10(-)4, human Hb = 0.177 x 10(-)4, mouse Alb = 2.68 x 10(-)4, rat Alb = 4.96 x 10(-)4, and human Alb = 5.19 x 10(-)4. These rate constants were used with BO-adduct measurements to assess the systemic doses of BO arising from benzene in vivo in published animal and human studies. Among rats receiving a single gavage dose of 400 mg of benzene/kg of body weight, the BO dose of 2.62 x 10(3) nM BO-h, predicted from Alb adducts, was quite similar to the reported AUC0-infinity = 1.09 x 10(3) nM BO-h of BO in blood. Interestingly, assays of Hb adducts in the same rats predicted a much higher dose of 14.7 x 10(3) nM BO-h, suggesting possible in situ generation of adducts within the erythrocyte. Doses of BO predicted from Alb adducts were similar in workers exposed to benzene [13.3 nM BO-h (mg of benzene/kg of body weight)-1] and in rats following a single gavage dose of benzene [8. 42 nM BO-h (mg of benzene/kg of body weight)-1]. Additional experiments indicated that crude isolates of Hb and Alb had significantly higher levels of BO adducts than dialyzed proteins, suggesting that conjugates of low-molecular-weight species were abundant in these isolates.

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“…Data are fromGlatt et al (1989),Whysner et al (2004),Stark and Rastetter (1996),Kirkland et al (2016), and Toxicology Data Network (2019). exchange; SHE, Syrian Hamster Embryo; w/out S9: tested with and without S9 metabolic activation.…”

mentioning

confidence: 99%

Utility of a next generation framework for assessment of genomic damage: A case study using the industrial chemical benzene

Luijten

Ball²,

Dearfield

et al. 2019

Environ and Mol Mutagen

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We recently published a next generation framework for assessing the risk of genomic damage via exposure to chemical substances. The framework entails a systematic approach with the aim to quantify risk levels for substances that induce genomic damage contributing to human adverse health outcomes. Here, we evaluated the utility of the framework for assessing the risk for industrial chemicals, using the case of benzene. Benzene is a wellstudied substance that is generally considered a genotoxic carcinogen and is known to cause leukemia. The case study limits its focus on occupational and general population health as it relates to benzene exposure. Using the framework as guidance, available data on benzene considered relevant for assessment of genetic damage were collected. Based on these data, we were able to conduct quantitative analyses for relevant data sets to estimate acceptable exposure levels and to characterize the risk of genetic damage. Key observations include the need for robust exposure assessments, the importance of information on toxicokinetic properties, and the benefits of cheminformatics. The framework points to the need for further improvement on understanding of the mechanism(s) of action involved, which would also provide support for the use of targeted tests rather than a prescribed set of assays. Overall, this case study demonstrates the utility of the next generation framework to quantitatively model human risk on the basis of genetic damage, thereby enabling a new, innovative risk assessment concept. Environ.

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Structure-activity relationships in the mutagenicity and cytotoxicity of putative metabolites and related analogs of benzene derived from the valence tautomers benzene oxide and oxepin

Cited by 9 publications

References 42 publications

Dimethyldioxirane Converts Benzene Oxide/Oxepin into (Z,Z)-Muconaldehyde and sym-Oxepin Oxide: Modeling the Metabolism of Benzene and Its Photooxidative Degradation

Dimethyldioxirane Converts Benzene Oxide/Oxepin into (Z,Z)-Muconaldehyde and sym-Oxepin Oxide: Modeling the Metabolism of Benzene and Its Photooxidative Degradation

Formation of Hemoglobin and Albumin Adducts of Benzene Oxide in Mouse, Rat, and Human Blood

Utility of a next generation framework for assessment of genomic damage: A case study using the industrial chemical benzene

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