Formation of the food associated carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in model systems

Food-related mutagens play a major role in human carcinogenesis. Heterocyclic aromatic amines which are formed in meat or fish during cooking contribute to food-related carcinogenesis, at least in rodents. The mechanism of formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was clarified by using 13C-labelled phenylalanine as a reaction partner in a model system containing additionally creatinine. Isolation of the labelled reaction product (PhIP) and 13C-NMR experiments showed that the carbon atoms of phenylalanine form a part of the pyridine moiety. Carbon atoms C-5, C-6 and C-7 in PhIP originated quantitatively from phenylalanine, leading to the conclusion that PhIP is formed by a defined mechanism and that two phenylalanine molecules are needed to form PhIP in this model system. In the proposed mechanism phenylacetaldehyde plays a key role which undergoes an aldol condensation with creatinine. The six-membered pyridine ring is completed by formation of a Schiff’s base and cyclisation.