Oxidation Products of N-nitrosodialkylamines Generated by Fenton's Reagent in the Presence of Copper Are Direct Acting Mutagens

Abstract

N-Nitrosodialkylamines, activated metabolically by cytochrome P450, possess mutagenic and carcinogenic activity. In this study, the hydroxyl radical, generated from Fenton's reagent, was used as an oxidant for the activation of the N-nitrosodialkylamines. Ethyl acetate extract from the reaction mixture which included Fe²⁺-Cu²⁺-H₂O₂ and N-nitrosodialkylamines; N-nitrosodimethylamine (NDM), N-nitrosodiethylamine (NDE), N-nitrosodipropylamine (NDP), N-nitrosodibutylamine (NDB), N-nitroso-N-methylpropylamine (NMP), N-nitroso-N-methylbutylamine (NMB), were assayed for their mutagenicity in Salmonella typhimurium (S. typhimurium) TA1535 and Escherichia coli (E. coli) WP2 uvrA. Although Fenton's reagent (Fe²⁺-H₂O₂) alone did not activate NMB, the addition of the copper ion to the reaction with Fenton's reagent (Fe²⁺-Cu²⁺-H₂O₂) resulted in the production of mutagens. While the extracts of the reaction of NDM or NDE with Fe²⁺-Cu²⁺-H₂O₂ were not mutagenic, those of NMP, NDP, NMB, or NDB with Fe²⁺-Cu²⁺-H₂O₂ were mutagenic in both S. typhimurium TA1535 and E. coli WP2 uvrA. These results demonstrate that a direct-acting mutagen was formed from N-nitrosodialkylamines, with alkyl chains longer than propyl, by the oxidation in the Fe²⁺-Cu²⁺-H₂O₂ system.