METABOLISM OF FOOD-DERIVED HETEROCYCLIC AMINES IN NONHUMAN-PRIMATES

During the cooking of meats, several highly mutagenic heterocyclic ami nes (HCAs) are produced. Three HCAs, IQ, MeIQx, and PhIP have been und er study for carcinogenicity in cynomolgus monkeys, and to date, IQ ha s been shown to be a potent hepatocarcinogen. Concomitantly, the metab olic processing of these HCAs has been examined. Metabolism studies sh ow that the potent hepatocarcinogenicity of IQ is associated with the in vivo metabolic activation of IQ via N-hydroxylation and the formati on of DNA adducts. In monkeys undergoing carcinogen bioassay with IQ, N-hydroxylation was confirmed by the presence of the N-hydroxy-N-glucu ronide conjugate of IQ in urine. The N-hydroxylation of IQ appears to be carried out largely by hepatic CYP3A4 and/or CYP2C9/10, and not by CYP1A2, an isoform not expressed in liver of this species. Notably MeI Qx is poorly activated in cynomolgus monkeys and lacks the potency of IQ to induce hepatocellular carcinoma after a 5-year dosing period. Th e poor activation of MeIQx appears to be due to the lack of constituti ve expression of CYP1A2 and an inability of other cytochromes P450, su ch as CYP3A4 and CYP2C9/10, to N-hydroxylate the quinoxalines. MeIQx i s detoxified in monkeys largely by conjugation with glucuronide at the N-1 position, Although the carcinogenicity of PhIP is not yet known, the metabolic data suggest that PhIP will be carcinogenic in this spec ies. PhIP is metabolically activated in vivo in monkeys by N-hydroxyla tion, as discerned by the presence of the N-hydroxy-N-glucuronide conj ugate in urine, bile, and plasma. PhIP also produces DNA adducts that are widely distributed in tissues. The results from these studies supp ort the importance of N-hydroxylation in the carcinogenicity of HCAs i n nonhuman primates and by analogy, the importance of this metabolic a ctivation step in the possible carcinogenicity of dietary HCAs in huma ns.