Mutagenic activity of three isomeric N-nitroso-N-methylaminopyridines towards Escherichia coli K-12 in in vitro and animal-mediated assays

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Abstract
Three isomeric nitrosomethylaminopyridines (2-NMPY [2-nitrosomethylaminopyridine], 3-NMPY [3-nitrosomethylaminopyridine] and 4-NMPY [4-nitrosomethylaminopyridine]), of which only the 2-isomer exerts significant carcinogenic activity in rats, were tested in vitro and in the host-mediated assay for their activity to induce gene mutations in E. coli K-12 strain 343/113. Two related carcinogenic nitrosamines, nitrosodimethylamine (NDMA) and nitrosomethylaniline (NMA), were also tested. The in vitro mutagenicity tests were performed either without or in the presence of various fractions (S-9, microsomes, S-100) of rodent liver homogenates. The in vivo mutagenicity was determined in host-mediated assays, in which the indicator E. coli cells were recovered for the liver of treated animals. In experiments involving the S-9 liver fraction, only 2-NMPY among the nitrosomethylaminopyridines exerted a slight mutagenic effect. The low mutagenicity of this isomer, and the nonmutagenicity of the remaining 3- and 4-isomer could be partly explained in experiments involving microsomes and the S-100 fraction of rodent liver: 2-NMPY and 4-NMPY were activated to mutagenic factors by microsomes, but their mutagenic effect was completely abolished when S-100 was added. 3-NMPY was directly mutagenic for E. coli, but its mutagenic potential was also abolished when S-100 liver fraction was added to the incubation mixtures. NDMA was activated to mutagenic factors with both microsomes and S-9 fractions, whereas NMA was not mutagenically active under any of the present experimental conditions. The deactivating effect of the S-100 fraction was of nonenzymatic nature and probably was due to the presence of thiol-containing scavenger molecules in this fraction. In the host-mediated assays, only the 2-isomer among the 3 exerted a mutagenic affect. The 3 isomers investigated are mutagenic either directly (3-NMPY) or on microsomal activation (2-NMPY and 4-NMPY). The noncarcinogenicity of 3-NMPY and 4-NMPY and the nonmutagenicity of these compounds, in host-mediated assays are probably the result of very efficient deactivation by cytosolic (thiol group-containing?) factors.

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