title: Metabolic formation, synthesis and genotoxicity of the N-hydroxy derivative of the food mutagen 2-amino-1-methyl-6-phenylimidazo (4,5-b) pyridine (PhIP).
abstract: Hepatic microsomes from rats pretreated with PCB were found to metabolize the food mutagen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) to two major metabolites, one of which was identified as the N-hydroxy derivative, 2-hydroxy-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (N-OH-PhIP). This identification was based on mass spectral (MS), UV and HPLC data by comparison with N-OH-PhIP prepared by chemical synthesis, as well as the specific activity of the compound in the Ames Salmonella test. Synthetic N-OH-PhIP was prepared by catalytic reduction of the nitro derivative of PhIP, which was synthesized from PhIP by diazotization and reaction with sodium nitrite. N-OH-PhIP was mutagenic to Salmonella typhimurium TA98 without metabolic activation and had a specific mutagenic activity of 2700 revertants/nmol. N-OH-PhIP thus seems to be a proximate mutagenic metabolite of PhIP. Other direct acting mutagens were not detected in the microsomal incubation mixture after HPLC separation. N-OH-PhIP also induced sister chromatid exchange (SCE) in Chinese hamster ovary cells (CHO cells) without metabolic activation. The specific activity of N-OH-PhIP in this assay was approximately 3 times higher than the activity of PhIP with microsomal activation.
authors.affiliation: Institute of Toxicology, National Food Agency, Søborg, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Frandsen
authors.forename: E S
authors.initials: ES
authors.lastname: Rasmussen
authors.forename: P A
authors.initials: PA
authors.lastname: Nielsen
authors.forename: P
authors.initials: P
authors.lastname: Farmer
authors.forename: L
authors.initials: L
authors.lastname: Dragsted
authors.forename: J C
authors.initials: JC
authors.lastname: Larsen
mesh_terms: D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005502:Food; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens; D009154:Mutation; D009593:Nitroimidazoles / Q000737:chemistry; D011078:Polychlorinated Biphenyls; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000235:genetics; D012854:Sister Chromatid Exchange
chemical_list: D007093:Imidazoles; D009153:Mutagens; D009593:Nitroimidazoles; D011725:Pyridines; C060533:2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C069031:2-nitro-1-methyl-6-phenylimidazo(4,5-b)pyridine; C069032:2-(phenylazoxy)-1-methyl-6-phenylimidazo(4,5-b)pyridine; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D011078:Polychlorinated Biphenyls