Analysis of mutagenic activity and ability to induce replication of polyoma DNA sequences by different model metabolites of the carcinogenic tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) requires metabolic activation to express its carcinogenic activity. This activation leads to the formation of methylating and pyridyloxobutylating agents. To determine the possible biological effects mediated by each of these metabolic pathways we have studied the activities of model compounds that are metabolized to either a methylating or pyridyloxobutylating species. Each model compound was evaluated for its mutagenic activity in both prokaryotic and eukaryotic cell systems. The model compounds were also tested for their ability to induce asynchronous replication of viral DNA sequences. We demonstrate here that both the methylating model compound acetoxymethylmethylnitrosamine (AMMN) and the pyridyloxobutylating model compound 4-(acetoxymethyl)-1-(3-pyridyl)-1-butanone (NNKOAc) were mutagenic in strains TA98, TA100, and TA1535 but not TA102. While NNKOAc appeared to be 10 times more potent than AMMN in Salmonella, AMMN was found to be a more potent mutagen in mammalian G12 cells. Both chemicals could induce asynchronous replication of polyoma DNA sequences in rat fibroblast cells carrying an integrated copy of the polyoma virus with AMMN appearing to be more active. Measurement of DNA adduct levels suggest that the damage produced by NNKOAc was at least as active as that produced by AMMN when viewed on a per adduct basis. The possible implications of the biological activities exhibited by methylating and pyridyloxobutylating model compounds to NNK induced carcinogenesis are discussed.
Foiles
P G
PG
Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, NY 10595.
Peterson
L A
LA
Miglietta
L M
LM
Ronai
Z
Z
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D004249:DNA Damage; D004261:DNA Replication; D004279:DNA, Viral / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D011120:Polyomavirus / Q000235:genetics; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D002273:Carcinogens; D004279:DNA, Viral; D009153:Mutagens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone