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Mutagenicity of N--Acetoxyethyl-N-ethylnitrosamine and N,N-Diethylnitrosamine in Relation to the Mechanisms of Metabolic Activation of Dialkylnitrosamines¹

Department of Genetics, Institute of Cancer Research, Pollards Wood Research Station, Nightingales Lane, Chalfont St. Giles, Buckinghamshire HP8 4SP, United Kingdom

The mutagenicities of N--acetoxyethyl-N-ethylnitrosamine and N,N-diethylnitrosamine were compared in Drosophila for an assessment of the role of -carbon ethyl oxidation in the toxicological activition of the amine. The relative genetic potencies of the two compounds were deduced from regression studies of the mutation frequencies on molar dose for the whole testicular tissue with respect to the induction of the overall X-chromosome recessives (lethals and visibles), representatives of the RNA genes (especially ribosomal DNA), and six specific euchromatic loci.

Genetic activity per unit molar dose was invariably higher for the acetoxy compound than for the parent amine, but the two agents produced comparable mosaicism among corresponding mutational classes. This indicated that the same mutagenic reactive species were generated from the two agents, but more readily from the acetoxy derivative, which accorded with the hypothesis of nitrosamine metabolic activation through -carbon alkyl hydroxylation.

The differentials for the higher activity of the acetoxy compound varied between mutational classes: 20-fold for the X-chromsome recessives collectively or per locus, but only 5-fold for the specific ribosomal DNA deletions. These relationships indicated that the mutagenicities of these compounds were not entirely an outcome of DNA ethylation but were readily explicable on the basis of the additional generation of difunctional nitrosaldehydic metabolites, which were largely responsible for the induction of the ribosomal DNA deletions through DNA protein cross-linkage.

The higher mutagenicity of the acetoxy compound relative to the parent amine on ribosomal DNA was in part countered by its much lower selectivity index for these genes. The possible relevance of these genetic features to the carcinogenicities of these compounds was considered.

¹ This work was supported by grants to the Institute of Cancer Research (Chester Beatty Research Institute, Royal Cancer Hospital) from the Medical Research Council and the Cancer Research Campaign.

Received 5/27/76. Accepted 8/ 9/76.