Studies of the metabolic bioactivation of n-nitrosopyrrolidine in the rat.
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.
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation; D020111:Chlorodiphenyl (54% Chlorine); D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D009242:N-Nitrosopyrrolidine / Q000378:metabolism*; D009602:Nitrosamines / Q000378:metabolism*; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D001140:Aroclors; D009153:Mutagens; D009602:Nitrosamines; D020111:Chlorodiphenyl (54% Chlorine); D011335:Proadifen; D010882:Piperonyl Butoxide; D009242:N-Nitrosopyrrolidine