In vitro metabolism of N-nitrodialkylamines

The in vitro metabolism of N-nitramines was investigated in order to compare it with that of N-nitrosamines and to elucidate the mode of mutagenic action. N-Nitrodibutylamine (NO2DBA) and N-nitrodiethylamine (NO2DEA) were incubated with liver microsomes and hepatocytes prepared from rats treated with phenobarbital, and the products were analyzed by high-performance liquid chromatography and gas-liquid chromatography. The in vitro metabolic pattern of these nitramines was similar to that of the corresponding nitrosamines, except that N-nitro-N-alkylamines (produced via alpha-hydroxylation) were identified after incubation of the nitrodialkylamines. In the case of NO2DBA, besides N-nitro-N-butylamine, several nitramines produced by omega, omega-1, and omega-2 oxidations were identified as metabolites. NO2DBA and NO2DEA were mutagenic to Escherichia coli WP2 hcr- but not to Salmonella typhimurium TA1535. They were mutagenic only in the presence of hepatic microsomes, whereas their metabolites, N-nitro-N-butylamine and N-nitro-N-ethylamine, were direct mutagens. Thus, N-nitrodialkylamines are also metabolically activated to mutagens through alpha-hydroxylation.