Ruthenium porphyrin and oxidant convert N-nitrosodialkylamines into direct-acting mutagen in the Ames assay

Abstract

The Ames assay is used for short-term screening of mutagens/carcinogens that induce DNA damage. Most mutagens/carcinogens require enzymatic activation through oxidation by cytochrome P450 in an S-9 mix to exert their mutagenicity. Chemical models for cytochrome P450, consisting of water-soluble or water-insoluble iron porphyrin plus an oxidant, have been used to produce frameshift mutagens from aromatic amines, heterocyclic amines and polyaromatic hydrocarbons. In this study, the mutagenicity of N-nitrosodialkylamines was assayed in the presence of a chemical model, which consists of 5,10,15,20-tetrakis(2,4,6-trimethylphenyl)porphyrinatoruthenium(IV) dichloride (RuMe₃) and 2,6-dichloropyridine N-oxide (Cl₂pyNO). The chemical model activated symmetrical N-nitrosodialkylamines (alkyl = methyl, ethyl, propyl, butyl), and unsymmetrical N-nitroso-N-methylalkylamine (alkyl = propyl, butyl) in Salmonella typhimurium YG7108. Furthermore, the mutagenicity of N-nitrosodipropylamine (NDP) in S. typhimurium YG7108 was higher than that in S. typhimurium TA1535, suggesting that the mutagenicity derived from NDP using the chemical model was due to DNA alkylation. The results showed that the chemical model can activate N-nitrosodialkylamines to induce base substitution mutations.