Investigations on the mutagenicity of primary and secondary α-acetoxynitrosamines with Salmonella typhimurium: activation and deactivation of structurally related compounds by S-9

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Abstract
α-Acetoxynitrosamines may serve as model compounds to study mechanisms of action of N-nitrosamines. They are readily cleaved through hydrolysis, or by esterases, to yield the same ultimate, reactive species presumably also arising after metabolic activation of N-nitrosamines. Structure-activity investigations on α-acetoxynitrosamines promise to aid in elucidating mechanisms involved during the activation of N-nitrosamines. A series of α-acetoxyalkylnitrosamines was therefore tested for mutagenicity with Salmonella typhimurium TA 1535. The compounds were readily cleaved, by hydrolysis, to mutagenic intermediates. When comparing compounds according to their proposed alkylating properties, unstable secondary a-acetates were considerably more mutagenic than the corresponding relatively stable primary α-acetates. Addition of S-9 mix caused both activation as well as deactivation in an unexpected structure-related pattern. This was so because an exactly opposite influence of S-9 components on the mutagenicity was observed for each pair of primary and secondary compounds containing the same alkylating species. Furthermore, pairs of compounds with both methylating and ethylating properties were differently influenced by S-9 addition than those with propylating or butylating effects. This dearly demonstrates how different chemical properties of intermediate forms may strongly influence the biological activity of otherwise quite similar compounds.