Effect of tryptamine on the mutagenic activity of 2-amino-3-methylimidazo(4,5-f) quinoline (IQ) and related azaarenes in the Ames test.
The bioactivation of the azaarenes 2-amino-3-methylimidazo(4,5-f) quinoline (IQ), 2-amino-3,4-dimethylimidazo(4,5-f) quinoline (MeIQ) and 2-amino-3,8-dimethylimidazo(4,5-f) quinoxaline (MeIQx) to mutagens by hepatic S9 preparations derived from Aroclor-pretreated Wistar rats was inhibited by tryptamine (2-50 microM). However, with similar preparations derived from Sprague-Dawley rats, bioactivation of IQ and MeIQx was less markedly inhibited by tryptamine while metabolic activation of MeIQ was enhanced. In the absence of cytosol, activation of IQ by microsomal preparations of both rat strains was inhibited by tryptamine. Cytosolic fractions from both rat strains were incapable of activation of IQ per se but increased the mutagenicity of the microsomal metabolite(s). This potentiation of the mutagenic activity by cytosol derived from Wistar rats was also inhibited by tryptamine whereas no significant inhibition was observed with cytosolic preparations from Sprague-Dawley rats. There appear to be two alternative pathways of microsomal metabolism of IQ: a tryptamine-sensitive pathway, probably involving the formation of the N-hydroxymetabolite; and a tryptamine-insensitive pathway producing weakly mutagenic or non-mutagenic metabolites which are activated to a potent mutagen by the cytosol. The tryptamine-insensitive pathway appears to be the major route of activation of the azaarenes in microsomal preparations from Sprague-Dawley rats and the principal activation route for MeIQ in both rat strains.
Abu-Shakra
A
A
Department of Biochemistry, University of Surrey, Guildford, UK.
Ioannides
C
C
Walker
R
R
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D020111:Chlorodiphenyl (54% Chlorine); D003600:Cytosol / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D011810:Quinoxalines / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014363:Tryptamines / Q000494:pharmacology*
D001140:Aroclors; D009153:Mutagens; D011804:Quinolines; D011810:Quinoxalines; D014363:Tryptamines; D020111:Chlorodiphenyl (54% Chlorine); C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C030820:tryptamine; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline