Investigations on the mutagenicity of primary and secondary alpha-acetoxynitrosamines with Salmonella typhimurium: activation and deactivation of structurally related compounds by S-9.
alpha-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 alpha-acetoxynitrosamines promise to aid in elucidating mechanisms involved during the activation of N-nitrosamines. A series of alpha-acetoxyalkynitrosamines 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 alpha-acetates were considerably more mutagenic than the corresponding relatively stable primary alpha-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 spices. 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 clearly demonstrates how different chemical properties of intermediate forms may strongly influence the biological activity of otherwise quite similar compounds.
D000447:Aldehydes / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D006207:Half-Life; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism
D000447:Aldehydes; D009153:Mutagens; D009602:Nitrosamines