| 6339097 |
Cottrell RC, Blowers SD, Walters DG, Lake BG, Purchase R, Phillips JC, Gangolli SD: Studies of the metabolic bioactivation of n-nitrosopyrrolidine in the rat. Carcinogenesis. 1983;4(3):311-4.
The metabolism of N-nitrosopyrrolidine (NPYR) to 4-hydroxybutanal (4-HB) (the first stable product of the putative alpha-hydroxylation pathway) and its bioactivation in the Ames bacterial mutagenicity test system were examined in the presence of a number of inhibitors. Both SKF 525A and piperonyl butoxide were found to be potent inhibitors of the production of 4-HB by rat liver microsomal preparations but were ineffective in the mutagenicity model with liver S-9 from either untreated or Aroclor 1254 pretreated rats. In addition two inhibitors of the mutagenic activity of N-nitrosodimethylamine (NDMA) in this system, 2-phenylethylamine and benzimidazole failed to reduce the activity of NPYR. These results suggest that the bioactivation of NPYR may proceed by processes other than the cytochrome P-450 dependent route generating 4-HB and the amine oxidase catalysed route implicated in NDMA activation. Evidence was also obtained of a second cytosol dependent bioactivation step involving a microsome generated pre-mutagen. This activity may be responsible, at least in part, for the enhancement by cytosol of the mutagen producing activity of liver microsomes from Aroclor 1254 pretreated (but not control) rats. |
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