Abstract
N-Nitrosodialkylamines are environmental alkylating carcinogens which are metabolically activated to α-hydroxy nitrosamines by cytochrome P450. The precise mechanism of their activation is not well understood, and a simplified chemical model for cytochrome P450 as a non-enzymatic system is useful for investigating the mechanism. In the present study, a chemical model was used in a bacterial mutation assay as a substitute of S9 mix, and its ability in the activation of N-nitrosodialkylamines was elucidated. In the presence of tetrakis (pentafluorophenyl) porphyrinatoiron (III) chloride and tert-butyl hydroperoxide, the mutagenicity of N-nitrosodialkylamines [alkyl=methyl (NDM), ethyl (NDE), propyl (NDP) and butyl (NDB)] in Salmonella typhimurium YG7108 was detected. The mutagenicity increased by the pre-incubation and was dependent on the concentration of mutagens. The mutagenic activity of N-nitrosodialkylamines in Salmonella typhimurium YG7108 was in the following order : NDB>NDM>NDE≈NDP. The formation of aldehydes derived from dealkylation in the present model was exemplified by the formation of acetaldehyde from NDE. These results showed that N-nitrosodialkylamines were activated by the model system, and consequent mutagenicity was observed. The oxidation by the model can mimic the metabolic activation of chemical carcinogens by cytochrome P450, and the biomimetic catalyst is useful in investigating the mechanisms of the metabolic pathway of N-nitrosodialkylamines.
