Metabolic processing and disposition of 2-amino-3-methylimidazo[4,5-f] quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in nonhuman primates.
The metabolic processing and disposition of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), three heterocyclic amine mutagens and carcinogens derived from cooked food, was examined in cynomolgus monkeys. IQ is an established hepatocarcinogen in cynomolgus monkeys; however, the carcinogenicity of MeIQx and PhIP is not yet known. IQ was extensively metabolized with little parent compound excreted in urine. Urinary metabolites of IQ arise from a combination of cytochrome P-450 mediated N-demethylation, N-hydroxylation, or ring oxidation at the C-5 position and conjugation with sulfate or glucuronide. IQ was also conjugated at the exocyclic amino group forming IQ-sulfamate and IQ-N-glucuronide. Enteric bacteria biotransformed IQ and its N-demethylated metabolite to 7-oxo-IQ and N-demethyl-7-oxo-IQ, respectively. N-Hydroxy-IQ-N-glucuronide was found in urine of monkeys indicating that metabolic activation via cytochrome P-450-mediated N-hydroxylation occurs in vivo and supporting the theory N-hydroxy-IQ plays a role in the initiation of IQ-induced hepatocarcinogenesis. At least eight urinary metabolites of MeIQx were seen in monkeys fed MeIQx. As was found with IQ, metabolites of MeIQx arise from conjugation with sulfate and glucuronide at the exocyclic amino group, and by cytochrome P-450 mediated oxidation at the C-5 position followed by conjugation with sulfate or glucuronide In contrast to IQ, a significant amount of the dose of MeIQx was excreted unchanged in the urine of monkeys. PhIP was extensively metabolized with a predominant route of metabolism being cytochrome P-450-mediated 4'hydroxylation followed by sulfate conjugation to form PhIP-4'-sulfate. No sulfate conjugation at the exocyclic amino group of PhIP was observed. An N-hydroxy-PhIP-N-glucuronide was also found in urine and bile indicating that metabolic activation of PhIP via N-hydroxylation occurs in vivo in monkeys and suggesting that PhIP may ultimately be carcinogenic to monkeys.
Snyderwine
E G
EG
National Cancer Institute, Bethesda, Maryland 20892-4255, USA.
Turesky
R J
RJ
Buonarati
M H
MH
Turteltaub
K W
KW
Adamson
R H
RH
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics; D003296:Cooking; D005502:Food; D006358:Hot Temperature; D007093:Imidazoles / Q000378:metabolism* / Q000493:pharmacokinetics; D008252:Macaca fascicularis; D009153:Mutagens / Q000378:metabolism* / Q000493:pharmacokinetics; D011804:Quinolines / Q000378:metabolism / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000378:metabolism* / Q000493:pharmacokinetics
D002273:Carcinogens; D007093:Imidazoles; D009153:Mutagens; D011804:Quinolines; D011810:Quinoxalines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine