title: Metabolism of heterocyclic aromatic amines and strategies of human biomonitoring.
abstract: The metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), two carcinogenic heterocyclic aromatic amines (HCAs) formed in cooked meats and fish, was studied in animal models and in vitro with human tissues to develop strategies for human biomonitoring. Both IQ and MeIQx are rapidly absorbed from the gastrointestinal tract of rodents and transformed into a number of products which are excreted in urine and feces. Detoxification occurs via cytochrome P450 mediated ring hydroxylation at the C-5 position followed by conjugation to sulfuric or beta-glucuronic acid. Other routes of detoxification include N2-glucuronidation and the uncommon pathway of sulfamate formation; N2-acetylation, however, appears to be a minor pathway. Metabolic activation by N-oxidation was demonstrated through formation of the metastable N2-glucuronide conjugate of the mutagenic N-hydroxy metabolites. These conjugates are excreted preferentially in urine rather than bile. Many of these metabolic pathways also exist in nonhuman primates. The binding of IQ and MeIQx to blood proteins is low and thus, human biomonitoring through protein adducts may be difficult. Human liver can metabolically activate HCAs by cytochrome P450 mediated N-oxidation and can also catalyze the detoxification of IQ and MeIQx through sulfamate formation; however, HCAs appear to be poor substrates for N-acetyltransferase. Preliminary data have shown that humans excrete both the N2-sulfamate and N2-glucuronide of MeIQx in urine following consumption of cooked meat. Thus, rodents, nonhuman primates and humans appear to have several common routes of HCA biotransformation.
authors.affiliation: Nestec Ltd., Nestle Research Centre, Lausanne, Switzerland.
authors.forename: R J
authors.initials: RJ
authors.lastname: Turesky
authors.forename: L B
authors.initials: LB
authors.lastname: Fay
authors.forename: D H
authors.initials: DH
authors.lastname: Welti
mesh_terms: D000818:Animals; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D003296:Cooking; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004784:Environmental Monitoring; D005399:Fishes; D006358:Hot Temperature; D006801:Humans; D008658:Inactivation, Metabolic; D007408:Intestinal Absorption; D008460:Meat; D009153:Mutagens / Q000378:metabolism*; D011323:Primates; D011804:Quinolines / Q000378:metabolism* / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000378:metabolism* / Q000493:pharmacokinetics; D012377:Rodentia
chemical_list: D001798:Blood Proteins; D002273:Carcinogens; 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; D003577:Cytochrome P-450 Enzyme System