Metabolism of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in nonhuman primates undergoing carcinogen bioassay.
2-Amino-3-methylimidazo[4.5-f]quinoline (IQ) is a potent bacterial mutagen and rodent carcinogen which also produces hepatocellular carcinoma in monkeys. The metabolism and disposition of this procarcinogen were investigated in monkeys undergoing carcinogen bioassay and in monkeys given an acute dose of IQ. Analysis of urine, feces, and bile revealed that IQ was extensively metabolized. A number of metabolites in urine were purified by high-performance liquid chromatography and characterized by 1H NMR and mass spectroscopy. Metabolites resulted from cytochrome P450-mediated ring oxidation at the C-5 position or N-demethylation. These metabolites could be further transformed by conjugation to sulfate or beta-glucuronic acid. Glucuronidation and sulfamate formation at the exocyclic amine group were other major routes of metabolism. Enteric bacteria also contributed to IQ biotransformation by forming the 7-oxo derivatives of IQ and N-demethyl-IQ. The metastable N2-glucuronide conjugate of the carcinogenic metabolite, 2-(hydroxyamino)-3-methylimidazo[4,5-f]quinoline, was found in urine. This indicates that metabolic activation through cytochrome P450-mediated N-oxidation occurs in vivo and that glucuronidation is a means of transport of the carcinogenic metabolite to extrahepatic tissues.
Snyderwine
E G
EG
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892.
Welti
D H
DH
Fay
L B
LB
Würzner
H P
HP
Turesky
R J
RJ
D000818:Animals; D001646:Bile / Q000737:chemistry; D005243:Feces / Q000737:chemistry; D005260:Female; D005506:Food Contamination / Q000032:analysis*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D010084:Oxidation-Reduction; D011804:Quinolines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013056:Spectrophotometry, Ultraviolet
D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline