STRUCTURE-ACTIVITY-RELATIONSHIPS IN THE MUTAGENICITY AND CYTOTOXICITYOF PUTATIVE METABOLITES AND RELATED ANALOGS OF BENZENE DERIVED FROM THE VALENCE TAUTOMERS BENZENE OXIDE AND OXEPIN

A series of putative metabolites and related analogs of benzene, deriv ed from the valence tautomers benzene oxide and oxepin, was tested for mutagenicity (reversions to histidine prototrophy and forward mutatio ns to resistance to 8-azaguanine) and for cytotoxicity by the Ames Sal monella 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-sym-Oxepin oxide, which is a putati ve 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(5.10)undeca-1,6-diene, a stable bridgehead diene a nalog of sym-oxepin oxide, were toxic but not mutagenic in both assays . 4H-Pyran-4-carboxaldehyde, a stable acid catalyzed rearrangement pro duct of sym-oxepin oxide, was not mutagenic and much less cytotoxic th an sym-oxepin oxide. Stable analogs of the valence tautomer benzene ox ide, namely syn-indan-3a,7a-oxide and syn-2-hydroxyindan-3a,7a-oxide, were mutagenic and induced point mutations. All compounds were cytotox ic to Salmonella. Firstly, the apparent decoy times of these chemicals , especially that of sym-oxepin oxide, were surprisingly longer than e xpected, as judged by quantitative plate diffusion assays. Secondly, i t is concluded that if benzene oxide is further metabolized in its oxe pin tautomeric form, toxic but not mutagenic products are formed. Thir dly, the relatively weak mutagenicity of benzene oxide may be mainly d ue to its instability and corresponding low probability to reach intra cellular polynucleotide targets, whereas stable analogs of benzene oxi de are relatively more potent mutagens. (C) 1996 Wiley-Liss, Inc.