Evidence for penetration of the nuclear envelope by N-nitrosomethylhydroxymethylamine

The metabolic activation of N-nitrosamines to alkylating agents is mediated by the hydroxylation of the carbon adjacent to the N-nitroso moiety. The resulting N-nitroso-alpha-hydroxy-amines are unstable and decompose to an aldehyde or ketone and a syn-alkane diazotic acid, the latter species being responsible for the carbenium ion reactions associated with nitrosamine-induced alkylation of DNA. Since this chain of events is thought to be initiated in the cytoplasm, there must be a 'transportable' metabolite that can diffuse through the cytoplasm, penetrate the nuclear envelope and alkylate the DNA therein. The 'transportability' of N-nitrosomethylhydroxymethylamine, the putative proximate metabolite of N-nitrosodimethylamine, has been assessed by incubating N-nitroso- ([14C]-methyl)-methylacetoxymethylamine with intact rat liver nuclei in the presence and absence of esterase. The results obtained demonstrate the ability of the in-situ-generated N-nitroso-alpha-hydroxyamine to penetrate the nuclear envelope and confirm that these unstable metabolites are 'transportable' proximate carcinogens.