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
✍ Scribed by Avishay-Abraham Stark; William H. Rastetter
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 705 KB
- Volume
- 28
- Category
- Article
- ISSN
- 0893-6692
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✦ Synopsis
A series of putative metabolites and related analogs of benzene, derived from the valence tautomers benzene oxide and oxepin, was tested for mutage nicity (reversions to histidine prototrophy and forward mutations to resistance to 8-azaguanine) and for cytotoxicity by the Ames Salmonella mutagenicity test. Benzene was not mutagenic in either assay. The benzene oxide-oxepin system and benzene dihydrodiol induced point mutations but not frameshifts. 4,5-symOxepin oxide, which is a putative metabolite of the oxepin valence tautomer; 3,6diaza-cyclohexane-l,6-3,4dioxide, a synthetic p r e cursor of symoxepin oxide; and transoid4,l Idioxatricyclo(5.1 O)undeca-l,aiene, a stable bridge head diene analog of symoxepin oxide, were toxic but not mutagenic in both assays. 4HPyran-4carboxaldehyde, a stable acid catalyzed rearrangement product of symoxepin oxide, was not muta-genic and much less cytotoxic than symoxepin oxide. Stable analogs of the valence tautomer benzene oxide, namely syr~indan-3a,7a-oxide and syrr2-h~droxyindan-3a,7a-oxide, were mutagenic and induced point mutations. All compounds were cyte toxic to Salmonella. Firstly, the apparent decay times of these chemicals, especially that of symoxepin oxide, were surprisingly longer than expected, as judged by quantitative plate diffusion assays. Secondly, it is concluded that if benzene oxide is further metabolized in its oxepin tautomeric form, toxic but not mutagenic products are formed. Thirdly, the relatively weak mutagenicity of benzene oxide may be mainly due to its instability and corresponding low probability to reach intracellular polynucleotide targets, whereas stable analogs of benzene oxide are relatively more potent mutagens.