Structure-activity relationships in metabolism and mutagenicities of N-nitrosamines

The metabolism of a series of nitrosamines in vitro was monitored by measuring nitrogen production and was compared with mutagenesis by the same compounds, allowing separation of mutagenic potencies into metabolic and postmetabolic terms. The rate of nitrogen production from symmetrical di-n-alkyl and methylalkyl nitrosamines increased with increasing molecular weight. The cyclic nitrosamines N-nitrosopiperidine and N-nitrosopyrrolidine were metabolized slightly less rapidly than the most hydrophobic compounds, and N-nitrosomorpholine was metabolized at about half this rate. N-Nitrosomethylaniline was metabolized to nitrogen relatively slowly. Branching at the alpha-carbons reduced alpha-oxidative metabolism several fold. Substitution at the beta-carbon of N-nitrosodiethylamine or N-nitrosodi-n-propylamine with hydroxyl, cyano, oxo and methoxyl groups reduced metabolism to an even greater extent. Carboxyl substitution at the 4-position of N-nitrosopiperidine greatly reduced nitrogen formation, but 4-tert-butyl substitution had little effect. Effects of structure on mutagenic activities in Salmonella followed a different pattern. Higher homologue di-n-alkyl nitrosamines were more potent than lower homologues at lower doses, when potencies were taken from slopes of dose-response curves. However, when mutagenic potencies were expressed as 'mutagenic efficiencies' (revertants/mumol nitrogen), regardless of dose, the order of potency was N-nitrosodimethylamine greater than N-nitrosodiethylamine greater than N-nitrosodi-n-propylamine greater than N-nitrosodibutylamine. For the series of methylalkyl nitrosamines, mutagenic potencies were greatest for the higher molecular weight compounds, but they were all similar to that of N-nitrosodimethylamine when expressed as mutagenic efficiencies.(ABSTRACT TRUNCATED AT 250 WORDS)