Nitrosamine activation and detoxication through free radicals and their derived cations

The enzymatic activation of simple dialkylnitrosamines is widely perceived to involve cytochrome P450-mediated alpha-hydroxylation to generate an unstable alpha-hydroxynitrosamine. This process can also result in the denitrosation of the nitrosamine, presumably through a common intermediate. We present evidence that the critical intermediate is the alkynitrosaminomethyl free radical, which we generated by thermal decomposition of a nitrosamino acid perester. The radical rapidly loses NO to generate an N-alkylmethyleneimine. The radical is also produced during the Ce(IV) oxidation of beta-hydroxynitrosamines after fragmentation, where it not only loses NO but is oxidized further to a cation which reacts with water to form an alpha-hydroxynitrosamine. These results provide models of the activation and detoxication pathways for beta-oxidized nitrosamines.