PROSTAGLANDIN-H SYNTHASE MEDIATED METABOLISM AND MUTAGENIC ACTIVATIONOF 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 carcino gen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Incubation of C-14-l abeled 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 incub ations was stable and extractable with ethyl acetate. Upon fractionati on of such extracts by HPLC and subsequent analysis, two metabolites w ere 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-, H-1-NMR-spectroscopy, an d mass spectrometry of synthesized standards. Azo-IQ was obtained by c hemical oxidation of IQ with metasodium periodate. It was the major me tabolite in PHS incubations, but has not been detected in monooxygenas e incubations. Azo-IQ, without metabolic activation, was much less mut agenic in S. typhimurium YG1024 (308 rev/nmol) than nitro-IQ and 3-met hyl-2-nitroso-imidazo[4,5-f]quinoline (nitroso-IQ), two other S9-indep endent mutagens which have been synthesized by chemical oxidation of I Q with sodium nitrite. Nitro-IQ was formed only in trace amounts but d ue to its potent mutagenicity in S. typhimurium YG1024 (2 x 10(6) rev/ nmol) it accounted for most of the mutagenic activity of the incubatio ns. These data show that PHS-mediated in vitro metabolism of IQ result s in its metabolic activation; thus PHS may contribute to the genotoxi city of IQ in extrahepatic tissues.