Summary
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.
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Abbreviations
- NDphA:
-
nitrosodiphenylamine
- DphA:
-
diphenylamine
- DphAOH:
-
diphenylhydroxylamine
- Pb:
-
phenobarbital
- Cyt.:
-
cytochrome
- DMSO:
-
dimethylsulphoxide
- MNNG:
-
N-methyl-N′-nitro-nitrosoguanidine
- NDBA:
-
N-nitroso-di-n-butylamine
- ESR:
-
electron spin resonance
- NO:
-
nitric oxide
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Dedicated to Professor Erich Hecker on the occasion of his 60th birthday
This work is part of the theses of S. Görsdorf and T. Scheper
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Appel, K.E., Görsdorf, S., Scheper, T. et al. Metabolic denitrosation of diphenylnitrosamine: a possible bioactivation pathway. J Cancer Res Clin Oncol 113, 131–136 (1987). https://doi.org/10.1007/BF00391434
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DOI: https://doi.org/10.1007/BF00391434