Caffeine-derived N-nitroso compounds. III: Mutagenicity in S. typhimurium and in vitro induction of DNA single-strand breaks in rat hepatocytes by mononitrosocaffeidine and dinitrosocaffeidine.
Mutagenesis in S. typhimurium and in vitro induction of DNA single-strand breaks in primary rat hepatocytes (DNA-SSB) have been investigated for two new N-nitroso compounds, mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC). Mononitrosamidocaffeidine (MNAC) and tert.-(butyloxy)carbonyl-mononitrosamidocaffeidine (t-BOC-MNAC), both nitrosated derivatives of caffeidine with nitrosation at methylcarboxamide-N only, were also similarly studied. MNC, an asymmetric nitrosamine, failed to show mutagenicity in any of the tester strains used, and also did not induce DNA-SSB in rat hepatocytes. DNC, having both N-nitrosamide and N-nitrosamine groups in the molecule, showed direct mutagenicity in TA100, TA1535 and TA102. The mutagenic potential of the compound was found to increase on S9 activation. However, it was non-mutagenic in TA98 and TA1537. DNC also exhibited a high potential for inducing alkali-labile DNA-SSB in rat hepatocytes (70-78% C-T value) and was cytotoxic at concentrations over 0.1 mumole/ml. Both MNC and DNC were found to produce formaldehyde on S9 activation. MNAC was not mutagenic directly but showed weak mutagenicity on metabolic activation, whereas t-BOC-MNAC was mutagenic both with and without S9 activation in TA100, TA1535 and TA102. t-BOC-MNAC was more cytotoxic to hepatocytes than MNAC, though both caused DNA-SSB to the same extent (62% C-T value). On the basis of the presented data it is inferred that while DNC is a direct-acting mutagen in TA100, TA1535 and TA102 due to the presence of a reactive N-methylnitrosamido group, its mutagenic potential is greatly enhanced in the presence of S9 possibly due to the synergistic influence of an activated N-methylnitrosamino group in the molecule. Additionally, the study shows a qualitative consistency between Salmonella mutagenicity, genotoxicity in hepatocytes and the reactivity of the methyl group at the nitrosamido-N in nitrosated caffeidine compounds.
Erdinger
L
L
Hygiene Institute, University of Heidelberg, Germany.
Schmezer
P
P
Razdan
R
R
Kumar
R
R
Spiegelhalder
B
B
Preussmann
R
R
Siddiqi
M
M
D000818:Animals; D001711:Biotransformation; D002110:Caffeine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D002478:Cells, Cultured; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects*; D005557:Formaldehyde / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D009602:Nitrosamines / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects
D004277:DNA, Single-Stranded; D009153:Mutagens; D009602:Nitrosamines; C082387:mononitrosocaffeidine; C082388:dinitrosocaffeidine; C082389:tert-butyloxycarbonyl-mononitrosamidocaffeidine; D005557:Formaldehyde; D002110:Caffeine