Genotoxic activity of the N-acetylated metabolites of the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ).
The genotoxic potential of the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and their N-acetylated metabolites (AcIQ and AcMeIQ, respectively) has been studied, in order to evaluate whether an initial N-acetylation of IQ or MeIQ is important for the overall in vivo genotoxicity of the compounds. When incubated with uninduced (control) rat hepatocytes, both the acetylated and the unacetylated compounds appeared to be relatively stable, whereas water-soluble metabolites (i.e. not extractable by ethyl acetate at alkaline pH) were rapidly formed with hepatocytes from PCB-induced animals. No DNA damage was induced by IQ or MeIQ in hepatocytes isolated from control rats, as measured by alkaline elution. In hepatocytes from PCB-pretreated rats, IQ, MeIQ, AcIQ and AcMeIQ induced DNA damage at low (10(-6) M) concentrations, with AcIQ being more potent than IQ whereas AcMeIQ was less potent than MeIQ. Similar patterns were observed when unscheduled DNA synthesis was measured in hepatocytes. The compounds induced sister chromatid exchanges in Chinese hamster V79 cells with PCB-induced hepatocytes as activation system; IQ and AcIQ were equal while AcMeIQ had less activity than MeIQ. The compounds were also compared in bacterial mutagenesis test systems (Salmonella typhimurium TA98). With hepatocyte activation, AcIQ was slightly more potent than IQ, whereas AcMeIQ was markedly less mutagenic than MeIQ. With subcellular fractions as activation system (rat liver S9 or microsomes), the N-acetylated compounds were similar to or less mutagenic than their parent compounds. The mutagenic effects of AcIQ and AcMeIQ in bacteria with microsomal activation were markedly reduced by the deacetylase inhibitor paraoxon.(ABSTRACT TRUNCATED AT 250 WORDS)
Brunborg
G
G
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Holme
J A
JA
Alexander
J
J
Becher
G
G
Hongslo
J K
JK
D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D007093:Imidazoles; D009153:Mutagens; D011804:Quinolines; C032012:2-hydroxyamino-3-methylimidazolo(4,5-f)quinoline; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline