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. Heterocycl ic aromatic amines which are formed in meat or fish during cooking contribu te to food-related carcinogenesis, at least in rodents. The mechanism of fo rmation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was clari fied by using C-13-labelled phenylalanine as a reaction partner in a model system containing additionally creatinine. Isolation of the labelled reacti on product (PhIP) and C-13-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 c onclusion that PhIP is formed by a defined mechanism and that two phenylala nine molecules are needed to form PhIP in this model system. In the propose d mechanism phenylacetaldehyde plays a key role which undergoes an aldol co ndensation with creatinine. The six-membered pyridine ring is completed by formation of a Schiffs base and cyclisation. (C) 1999 Elsevier Science Ltd. AII rights reserved.