Heterocyclic amines, carcinogenicity

Turteltaub KW, Felton JS, Gledhill BL, et al. 1990. Accelerator mass spectrometry in biomedical dosimetry Relationship between low-level exposure and covalent binding of heterocyclic amine carcinogens to DNA. Proc Natl Acad Sci USA 87 5288-5292. 

Lin, D., Meyer, D., Ketter, B., Lang, N., and Kadlubar, R (1994). Effects of human and rat glutathione S-transferases on the covalent DMA binding of N acctoxy derivatives of heterocyclic amine carcinogens in vitro. Cancer Res. 54,4920-4926. 

Ghoshal, A. and Snyderwine, E., Excretion of food-derived heterocyclic amine carcinogens into breast milk of lactating rats and formation of DNA adducts in the newborn, Carcinogenesis, 14, 2199, 1993. 

Turteltaub, K.W., Felton, J.S., Gledhill, B.L, Vogel, ).S., Southon, J.R., Caffee, M.W., Finkel, R.C., Nelson, D.E., Proctor, I.D., and Davis, J.C. (1990) Accelerator mass spectrometry in biomedical dosimetry relationship between low-level exposure and covalent binding of heterocyclic amine carcinogens to DNA. Proc. Natl. Acad. Sci. USA, 87, 5288-5292. 

A su ested mode of action for the inhibitory effects of CLA on the initiation of cancer forms the interference of CLA with DNA adduct formation. Effects of CLA on 2-amino-3-methylimidazo [4,5] quinoline (IQ, heterocyclic amine carcinogen) induced DNA adduct formation in different organs in rats and mice have been reported, although CLA was not successful in inhibiting adduct formation in all organs (49, 50). The inhibition of tumor growth by CLA has been attributed to the induction of lipid peroxidation in cancer cells (but not in neutral, lipid-rich tissues) (38), although work by Banni has shown that CLA does not behave differently than other polyunsaturated fatty acids (51). 

Holder, C. L., Preece, S. W., Conway, S. C., Pu, Y. M., and Doerge, D. R. 1997. Quantification of heterocyclic amine carcinogens in cooked meats using isotope dilution liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry. Rapid Commun. Mass Spectrom. 11 1667-1672. 

Gorlewska-Roberts KM, Teitel CH, Lay JO, Jr., et al. Lactoperoxidase-catalyzed activation of carcinogenic aromatic and heterocyclic amines. Chem Res Toxicol 2004 17(12) 1659-1966. 

The enzyme can also catalyze the transfer of an acetyl group from an N-acetylated hydroxylamine (hydroxamic acid) to form an acetoxy product, i.e., an N to O transacetylation and this pathway does not require acetyl Co-A (12). A-hydroxy-4-acetylaminobiphenyl provides an example of this conversion as shown in Figure 7.7. The significance of this pathway is that it leads to the activation of the hydroxamic acid because acetoxy derivatives of aromatic amines are chemically reactive and many are carcinogens such as the heterocyclic amines formed when meat is heated to a high temperature, e.g., 2-amino-1-mcthyl-6-phenylirnidaz()[4,5-i ]pyri(linc. 

Presently about 20 different mutagenic and/or carcinogenic heterocyclic amines (HAs) have been isolated from various heat-processed foods. One class of these HAs is formed by pyrolysis of proteins or some amino acids. These HAs are amino-carbolines (Figure 13.7), and have been identified in grilled, broiled, baked, and fried meat and fish products, in meat sauces and bouillons, as well as in pyrolyzed proteins, glutamate, lysine, phenylalanine, tryptophan, ornithine, and creatine. 

Figure 13.7 Mutagenic and carcinogenic heterocyclic amines of the carboline group (a) AaC (2-amino-9//-p5Tido[2,3,-i)]indole), (b) norharman (9f/-pyrido[4,3-i)]indole), (c) Trp-P-1 (3-amino-l,4-dimethyl-57/-pyrido[4,3-/)]indole), (d) Glu-P-1 (2-amino-6-methyl-dipyrido[l,2-a 3, 2 -d]imidazole).

Figure 13.8 Mutagenic and carcinogenic heterocyclic amines (a) IQ (2-amino-3-methylimidazo[4,5-/ quinoline), (b) IQx (2-amino-3-methylimidazo[4,5-/ quinoxaline), (c) PhIP, (2-amino-l-methyl-6-phenylimidazo[4,5- ] pyridine), (d) 1,5,6-TMIP (2-amino-l,5,6-trimethylimidazo[4,5-6] p5ridine).

Some dietary practices are thought to contribute to cancer development (Table 21.7). For example, high-temperature cooking prodnces carcinogens such as heterocyclic amines and polycychc aromatic hydrocarbons, and storing food can allow microbial carcinogens, snch as aflatoxin, to be prodnced (see Figure 21.27). 

Chemistry of heteroarylnitrenium ions. Research in this area has been spurred by the apparent importance of heterocyclic amines produced during the cooking of protein-containing foods as a ubiquitous class of human carcinogens. This chemistry has been under investigation for only a short period of time. 

Other examples are carcinogenicity studies on complex mixtures (petroleum middle distillates, foundry fumes, pesticides, heterocyclic amines, diesel exhaust, and solid particles) neurotoxicity studies of mixtures of solvents alone or in combination with exposure to physical factors and toxicity stndies of outdoor air pollutants, focusing... 

Both NAT1 and NAT2 N-acetylate benzidine and O-acetylate the N-hydroxy metabolite. Because NAT2 and, to a lesser extent, NAT1 both show variation in the human population, this influences susceptibility to the carcinogenic effects of arylamines such as benzidine. With other aromatic amines, such as the heterocyclic amines found as food pyrolysis degradation products, N-acetylation is not favored, N-oxidation being the primary route followed by O-acetylation. This seems to take place in the colon. 

Nago, M. and T. Sugimura Food Rome Carcinogens Heterocyclic Amines, John Wiley Sons. Inc., New York. NY. 2000. 

Commonly used drugs (other than isoniazid) affected by NAT2 polymorphism were procainamide, hydralazine, dapsone, and sulfonamides with an increase of side effects in all cases. A selective substrate of NATl is -aminosalicylic acid (PAS), but its genetic variation was never clinically important (52). Because of such lack of importance, more attention is often paid to the fact that various industrial chemicals with carcinogenic potential, and mutagenic heterocyclic amines, are substrates of both N-acetyltransferases (53). The presence or absence of these transferases will determine some incidences of cancer (54). Attempts have been made to ascribe cancer incidences in different populations to acetyltransferase differences (55). 

A. Solyakov, K. Skog, and M. Jagerstad, Possible binding of carcinogenic/mutagenic heterocyclic amines to melanoidins, in Melanoidins in Foods and Health, Vol. 2, J. M. Ames (ed), European Communities, Luxembourg, 2001, 117-118. 

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