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

Journal Article · Tue Dec 31 04:00:00 EST 1996 · Environmental and Molecular Mutagenesis

DOI:https://doi.org/10.1002/(SICI)1098-2280(1996)28:3<284::AID-EM13>3.0.CO;2-B· OSTI ID:482357

Stark, A A; Rastetter, W H ^[1]

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1. Tel-Aviv Univ., Ramat-Aviv (Israel)

A series of putative metabolites and related analogs of benzene, derived from the valence tautomers benzene oxide and oxepin, was tested for mutagenicity (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 dihydrodial induced point mutations but not frameshifts. 4,5-sym-Oxepin oxide, which is a putative metabolite of the oxepin valence tautomer; 3,6-diazo-cyclohexane-1,6-3,4-dioxide, a synthetic precursor of sym-oxepin oxide; and transoid-4,11-dioxatricyclo(5.1 0)undeca-1,6-diene, a stable bridgehead diene analog of sym-oxepin oxide, were toxic but not mutagenic in both assays. 4H-Pyran-4-=carboxaldehyde, a stable acid catalyzed rearrangement product of sym-oxepin oxide, was not mutagenic and much less cytotoxic than sym-oxepin oxide. Stable analogs of the valence tautomer benzene oxide, namely syn-indan-3a,7a-oxide and syn-2-hydroxyindan-3a,7a-oxide, were mutagenic and induced point mutations. All compounds were cytotoxic to Salmonella. Firstly, the apparent decay times of these chemicals, especially that of sym-oxepin 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. 48 refs., 4 figs., 3 tabs.

• OSTI ID: 482357
• Journal Information: Environmental and Molecular Mutagenesis, Journal Name: Environmental and Molecular Mutagenesis Journal Issue: 3 Vol. 28; ISSN EMMUEG; ISSN 0893-6692
• Country of Publication: United States
• Language: English

Related Subjects

56 BIOLOGY AND MEDICINE
APPLIED STUDIES
ANIMAL CELLS
BENZENE
GENETIC EFFECTS
METABOLITES
MUTAGENS
MUTATIONS
STRUCTURE-ACTIVITY RELATIONSHIPS