Alternative bioactivation routes for beta-hydroxynitrosamines. Biochemical and chemical model studies

The biochemical retroaldol-like fragmentation of beta-hydroxynitrosamines has been investigated further. The extent of fragmentation of 2-hydroxy-2-methylpropyl-methylnitrosamine (HMPMN) to N-nitrosodimethylamine and acetone induced by metabolic activation increases as the NADPH level is decreased. 2-Hydroxy-2-phenylethyl-methylnitrosamine (HPhEMN) undergoes competitive oxidation to 2-oxy-2-phenylethyl-methylnitrosamine (OPhEMN) and fragmentation to benzaldehyde and N-nitroso-dimethylamine in the presence of a metabolic activation system from rat liver. The extent of the oxidation was increased by preinduction of the rats with phenobarbital, or separate addition of NADPH and NAD, but was decreased by addition of dimethyl sulfoxide. The fragmentation was observed most readily when oxidation was inhibited or was not induced by cofactors. When HPhEMN was administered to a rat intraperitoneally, benzaldehyde (fragmentation) was found in the urine with OPhEMN and the substrate, but only the last two substances were found in liver and blood. These experiments provide evidence for retroaldol-like fragmentation of beta-hydroxynitrosamines both in vitro and in vivo. In a related investigation, it was found that N-nitroso-N-4-chlorophenyl-2-aminoethanal (NCAE) is extremely reactive and induces spontaneous generation of 4-chlorobenzenediazonium ion in chloroform, as trapped by 2-naphthol. NCAE reacts with dimethylamine in chloroform, benzene or methanol to give N-nitrosodimethylamine and 4-chloroaniline, among other products. This suggests that beta-nitrosaminoaldehydes produced by the biooxidation of their corresponding alcohols could produce cell alteration through alkylation, deamination or transnitrosation.