title: Metabolic denitrosation of diphenylnitrosamine: a possible bioactivation pathway.
abstract: Nitrosodiphenylamine was tested for induction of DNA single strand breaks in rat hepatocytes and Chinese hamster V 79 cells with the alkaline filter elution assay. While in rat hepatocytes DNA damage was observed, negative results were obtained in V 79 cells. In view of the metabolic capacity of hepatocytes and the chemical structure of nitrosodiphenylamine it seems likely that cytochrome P-450-dependent, reductive denitrosation might be necessary for exerting this effect. Therefore the metabolism of nitrosodiphenylamine was investigated in phenobarbital-induced mouse liver microsomes and some of the metabolites were also tested. One metabolite was identified as diphenylamine whereas the others were identified as a ring-hydroxylated derivative of diphenylamine and its corresponding quinoneimine. Diphenylhydroxylamine which was not detected in the microsomes as a metabolite produced a significant amount of DNA single strand breaks in V 79 cells. When diphenylhydroxylamine was incubated with microsomes electron spin resonance spectrum was observed which indicated the formation of the diphenylnitroxide radical. This radical seems to be mediated by auto-oxidation rather than by enzymatic catalysis. Whether diphenylhydroxylamine might be responsible for the observed genetoxic effects of nitrosodiphenylamine assumed to be produced via active oxygen species is discussed.
mesh_terms: D000818:Animals; D001711:Biotransformation; D006224:Cricetinae; D004249:DNA Damage; D004578:Electron Spin Resonance Spectroscopy; D006900:Hydroxylation; D008099:Liver; D008862:Microsomes, Liver / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism* / Q000633:toxicity; D051381:Rats
chemical_list: D009602:Nitrosamines; C023649:N-nitrosodiphenylamine