Amines, carcinogenic activity

Recently nitrosamines have attracted attention because of their marked carcinogenic activity in a wide variety of animal species Q, ). Nitrosamines are likely to be carcinogens in man as well human exposure to these compounds is by ingestion, inhalation, dermal contact and vivo formation from nitrite and amines Nitrite and amines react most rapidly at an acidic pH A variety of factors, however, make nitrosation a potentially important reaction above pH 7 these include the presence of microorganisms, and the possibilities of catalysis by thiocyanate, metals and phenols, and of transnitrosation by other nitroso compounds. 

High levels of retinol or retinyl acetate inhibit mutagenicity induced by aromatic amines in a Salmonella/mammalian microsome assay when carcinogen activation is carried out by S9 or purified microsomes ... 

Sesamin, however, did not significantly reduce the number of N-nitrosobis-(2-oxopropyl)-amine(DOP)-induced pancreatic cancer in hamsters (150). It was noticed that 2% sesamol in the diet exerts forestomach carcinogenic activity in rats and mice (151). Fortunately, human beings do not have a forestomach and daily ingestion of sesamol is much lower than 2%. 

C8. Clayson, D. B., JuU, J. W., and Bonser, G. M., The testing of ortho hydroxy-amines and related compounds by bladder implantation and a discussion of their structural requirements for carcinogenic activity. Brit. J. Cancer 12, 222-230 (1958). 

Fig. 1. Role of Resonance Stabilization in Contributing to Carcinogenic Activity of Aromatic Amines.

The 2 CYPIA proteins have been isolated from the livers of a number of animal species, purified, and shown to share extensive structural similarity and to display similar substrate specificity. The human orthologue of CYP1A2 has been isolated from liver and shown to metabolize the same substrates, and to play the same role in carcinogen activation, as the rodent proteins [9]. The human CYPlAl has not been purified but it has been expressed in mammalian cells like the rodent orthologue, it catalyses the oxidation of polycyclic aromatic hydrocarbons and the N-oxidation of aromatic amines [10]. This apparent similarity in substrate specificity between the human and rodent CYPIA proteins would indicate that where CYPIA is involved, toxicological data can, in principle, be extrapolated to man with more confidence. Of the cytochrome P450 proteins so far characterized, the CYPl family appears to be the most conserved within the phylogenetic tree [11]. 

Of all the short-term assays, the Ames Salmonella test is clearly the best validated and most widely used and will continue to be so for a number of years to come. The assay has an excellent record for identifying organic carcinogens, particularly carcinogens which are in the aromatic amine and polycyclic hydrocarbon classes. " In addition, positive results in the Ames assay and several other short-term mutagenesis assays, have been predictive of carcinogenic activity in rodent assays for a number of compounds with widespread human exposure. Examples of these include the food preservative furylfuramide AF-2 which was used extensively in Japan from 1965 to about 1977 the flame-retardant tris-B-P (tris[2,3-dibromopropyl]phosphate) which was used to treat children s sleepwear from 1972 to 1977 and aromatic amine components of hair dye preparations. 

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