Mutagenic activity of three isomeric N-nitroso-N-methylaminopyridines towards Escherichia coli K-12 in in vitro and animal-mediated assays.
Three isomeric nitrosomethylaminopyridines (2-NMPY, 3-NMPY, and 4-NMPY), 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 were also tested, namely, nitrosodimethylamine (NDMA) and nitrosomethylaniline (NMA). 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 non-mutagenicity 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, on the other hand, was directly mutagenic for E. coli but, again, its mutagenic potential was 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 could not be shown as mutagenically active under any  of the present experimental conditions. It could be shown that 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 three exerted a mutagenic affect. The present results indicate that the three isomers investigated here are mutagenic either directly (3-NMPY) or upon microsomal activation (2-NMPY and 4-NMPY). The non-carcinogenicity of 3-NMPY and 4-NMPY, and the non-mutagenicity of these compounds in host-mediated assays, is probably the result of very efficient deactivation by cytosolic (thiol-group-containing?)factors.
D000418:Albumins / Q000494:pharmacology; D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation; D003545:Cysteine / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000378:metabolism; D009602:Nitrosamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000418:Albumins; D001140:Aroclors; D009153:Mutagens; D009602:Nitrosamines; C018351:4-nitrosomethylaminopyridine; C018350:3-nitrosomethylaminopyridine; C018349:2-nitrosomethylaminopyridine; D003545:Cysteine