Prostaglandin-H synthase mediated metabolism and mutagenic activation of 2-amino-3-methylimidazo [4,5-f] quinoline (IQ).
Prostaglandin-H synthase (PHS), a mammalian peroxidase of interest for the extrahepatic formation of reactive intermediates of carcinogens, catalyzes in vitro the metabolic activation of the mutagen and carcinogen 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ). Incubation of 14C-labeled IQ with ram seminal vesicle microsomes (RSVM), a rich source of PHS, resulted in protein binding and generated products mutagenic in S. typhimurium YG1024. The mutagenic activity produced in IQ/PHS incubations was stable and extractable with ethyl acetate. Upon fractionation of such extracts by HPLC and subsequent analysis, two metabolites were identified as 2,2'-azo-bis-3-methylimidazo[4,5-f]quinoline (azo-IQ) and 3-methyl-2-nitro-imidazo[4,5-f]quinoline (nitro-IQ) confirmed by comparison of HPLC retention times, UV/VIS-, 1H-NMR-spectroscopy, and mass spectrometry of synthesized standards. Azo-IQ was obtained by chemical oxidation of IQ with meta-sodium periodate. It was the major metabolite in PHS incubations, but has not been detected in monooxygenase incubations. Azo-IQ, without metabolic activation, was much less mutagenic in S. typhimurium YG1024 (308 rev/nmol) than nitro-IQ and 3-methyl-2-nitroso-imidazo[4,5-f]quinoline (nitroso-IQ), two other S9-independent mutagens which have been synthesized by chemical oxidation of IQ with sodium nitrite. Nitro-IQ was formed only in trace amounts but due to its potent mutagenicity in S. typhimurium YG1024 (2 x 10(6) rev/nmol) it accounted for most of the mutagenic activity of the incubations. These data show that PHS-mediated in vitro metabolism of IQ results in its metabolic activation; thus PHS may contribute to the genotoxicity of IQ in extrahepatic tissues.
Wolz
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Institut für Toxikologie und SFB 172, Universität Würzburg, Germany.
Wild
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Degen
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D000818:Animals; D001711:Biotransformation; D066298:In Vitro Techniques; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011804:Quinolines / Q000378:metabolism* / Q000633:toxicity; D012486:Salmonella typhimurium / Q000235:genetics; D012669:Seminal Vesicles / Q000378:metabolism; D012756:Sheep
C093112:2,2'-azo-bis-3-methylimidazo(4,5-f)quinoline; D009153:Mutagens; D011804:Quinolines; C071417:2-nitro-3-methylimidazo(4,5-f)quinoline; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D011451:Prostaglandin-Endoperoxide Synthases