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Chapter 25 Toxicological Aspects of Aromatic Heterocyclic Amines
707
CHAPTER 25
Toxicological Aspects of Aromatic Heterocyclic Amines 25.1.
HETEROCYCLIC AROMATIC AMINES
General aspects A number of heterocyclic aromatic amines (HAAs) are formed by pyrolytic processes particularly from amino acids in pure form, but also from amino acids and other nitrogenous compounds in interaction with sugars and creatinine. HAAs are also generated by pyrolysis from more complex mixtures containing nitrogenous materials like proteins, but without the possibility to determine the precise origin of the HAAs. Since HAAs are mutagenic and suspected carcinogens in humans, and because amino acids and sugars are common in food, the presence of HAAs in food is of particular concern. Some aspects regarding the formation of aromatic heterocyclic amines were discussed in Sections 13.5, 18.1, and 21.2. A considerable amount of information on the presence of HAAs in food, smoke, and environment is reported in the literature [1–31]. The information is also summarized in excellent reviews [27,32–35] and in at least one monograph [36]. Several studies were focused on mutagenic properties of HAAs [32]. These compounds are generated in food when it is cooked at temperatures over 150 1C. The range of HAAs levels is between 0.1 ppb and 50 ppb, depending on the food and cooking conditions. The HAAs are not only present in cooked red meat, fish, and chicken, but also at lower levels in baked and fried foods derived from grain. Mutagenicity of fried beef hamburgers cooked at 230 1C was determined to be 800737 TA98 revertants per gram of cooked material [32] in the Ames/Salmonella test. In the tested fried beef, the reported level of 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx) was 3.072.0 ng/g, of 2-amino-3,4, 8-trimethyl-imidazo[4,5-f]quinoxaline (DiMeIQx) was 1.070.18 ng/g, of 2-amino-3-methyl-imidazo[4,5f]quinoline (IQ) was 0.0670.03 ng/g, and of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was 9.6 ng/g. HAAs were capable of producing both reverse and forward mutations in Salmonella bacteria and forward mutations in Chinese hamster ovary cells (CHO). The number and type of mutations depended on the repair capacity of the cells for both Salmonella and CHO. Also, there were statistically significant increases in the mutations in the pancreas of the ‘‘mutamouse’’ following PhIP exposure. Based on findings from studies on multiple species of experimental animals it was shown that heterocyclic amines produced cancer in multiple organs including forestomach, cecum, colon, liver, oral cavity, Zymbal gland, mammary gland, and skin. Although evidence from human epidemiology suggests that consumption of well-done or grilled meat (which may contain HAAs) may be associated with increased cancer risk, the data are insufficient to support the conclusion that this risk is due specifically to certain HAAs present in these foods. The list of some heterocyclic amines (including two heterocyclic compounds, harman, and norharman) together with their most common origin is given in Table 25.1.1. The list of detected HAAs is not limited to those listed in Table 25.1.1. Other similar compounds, such as tetrahydro-b-carbolines [37] were reported in specific samples. Studies on HAAs were also directed toward the measuring of certain markers of exposure to these compounds [38]. For example, after ingestion by different animals, only a few percent of the initial levels of MeIQx and PhIP were excreted as parent compounds. It was determined that urinary levels of parent HAA reflect only recent exposure. The excreted glucuronide conjugates of N-hydroxy-PhIP and N-hydroxy-MeIQx could be markers for the N-hydroxylation capacity and HAA exposure. 5-OH-PhIP can be considered a metabolite marker for PhIP, since it is formed from this compound as a by-product along with the formation of PhIP-DNA adducts. PhIP also gives adducts of serum albumin and hemoglobin. In mice, PhIP is irreversibly incorporated in a dose-dependent manner into hair. In humans exposed to an ordinary diet it was found that the level of PhIP can vary from o50–5000 pg PhIP/g hair.
708
Pyrolysis of Organic Molecules
TABLE 25.1.1. Heterocyclic amines of health concern and their most likely source following pyrolysis Likely pyrolytic origin
Reference
Soybean globulin
1, 5, 6, 16, 19, 20
Acronym
Compound
AaC
2-Amino-9H-pyrido[2,3-b]indole
4-CH2OH-8-MeIQx
2-Amino4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline
Cre-P-1
4-Amino-1,6-dimethyl-2-methylamino-1H,6Hpyrrolo[3,4-f]benzimidazol2-5,7-dione
Proteins
27
4,8-DiMeIQx
2-Amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline
Fried beef
27
7,8-DiMeIQx
2-Amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline
27
7,9-DiMeIgQx
2-Amino-1,7,9-trimethylimidazo[4,5-f]quinoxaline
27
16–18, 26
1,6-DMIP
2-Amino-1,6-dimethylimidazo[4,5-b]pyridine
Glu-P-1
2-Amino-6-methyldipyrido[1,2-a: 3u, 2u-d]imidazole
Glutamic acid
27
Glu-P-2
2-Aminodipyrido[1,2-a:3u2u-d]imidazole
Glutamic acid
10, 13–15
Harman
1-Methyl-9H-pyrido[3,4-b]indole
Coffee
20, 23, 24
IFP
2-Amino-1,6-dimethylfuro[3,2-e]imidazo[4,5-b]pyridine
IQ
2-Amino-3-methylimidazo[4,5-f]quinoline
Broiled sardines
10, 25
IQx
2-Amino-3-methylimidazo[4,5-f]quinoxaline
Lys-P-1
3,4-Cyclopentenopyrido[3,2-a]carbazole
Lysine
27
MeAaC
2-Amino-3-methyl-9H-pyrido[2,3-b]indole
Soybean globulin
1, 5, 6, 10, 16
10, 13–15, 18
22, 27 21, 28
MeIQ
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline
Broiled sardines
18
8-MeIQx
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline
Fried beef
1, 18, 22, 25, 26
4-MeIQx
2-Amino-3,4-dimethylimidazo[4,5-f]quinoxaline
Fried beef
1, 18, 22, 25, 26
1-Methyl-6-phenylimidazolo[4,5-b]pyridine-2-ylamine
Alanine?
27
Norharman
9H-Pyrido[3,4-b]indole
Coffee
13, 15, 20, 23, 24
Orn-P-1
4-Amino-6-methyl-1H-2,5,10,10b-tetraazafluoranthene
Ornithine
27
4uOH-PhIP
2-Amino-1-methyl-6-(4-hydroxyphenyl)imidazo[4,5b]pyridine
Phe-P-1
2-Amino-5-phenylpyridine
Phenylalanine
2, 27
PhIP
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Smoke
11, 19, 22, 25
1,5,6-TMIP
2-Amino-1,5,6-trimethylimidazo[4,5-b]pyridine
Trp-P-1
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole
Tryptophan
Trp-P-2
3-Amino-1-methyl-5H-pyrido[4,3-b]indole
Tryptophan
TriMeIQx
2-Amino-3,4,7,8-tetramethylimidazo[4,5-f]quinoxaline
27
27 1, 2, 5–7 2, 5–7, 10 27
It was suggested that this measurement could provide an indication of the level of exposure to PhIP [38]. Other studies attempted to find the metabolic path of HAAs [28,39]. It is likely that the first step in metabolic activation of mutagenic and carcinogenic heterocyclic amines is N-hydroxylation by cytochrome P-448. N-hydroxyamino compounds are further activated to form N-O-acyl derivatives that readily react with DNA. The adducts between the metabolites of Trp-P-2 and Glu-P-1, and DNA were shown to have a C8-guanylamino structure [39]. In the case of Glu-P-1, modification of guanine in GC clusters occurs preferentially. It was shown also that glutathione transferases and myeloperoxidase inactivated some heterocyclic amines or their active metabolites [39]. Also, hemin and fatty acids bind to HAAs and inactivate them. Fibers and other factors from vegetables also work to inactivate heterocyclic amines. Nitrite at low pH degraded some heterocyclic amines, but those with an imidazole moiety were found to be resistant. Glu-P-1 induced intestinal tumors in a high incidence when fed orally to rats.
Toxicological aspects of aromatic heterocyclic amines
709
When 14C-Glu-P-1 was administered by gavage into rats, about 50% and 35% were excreted into feces and urine, respectively, within 24 h. When the bile was collected, around 60% of radioactivity was found excreted into it within 24 h. In the bile, N-acetyl-Glu-P-1 was identified as one of the metabolites of Glu-P-1 [39]. In a different study [40], the metabolic activation of IQ to mutagenic intermediates in the Ames test was studied with hepatic activation systems from control and IQ-treated rats. Hepatic S9 preparations from IQ-treated rats were more efficient than the control in converting IQ to mutagens. An increase was seen also when isolated microsomes were employed as activation systems, but this was less pronounced. The microsome-mediated mutagenicity of IQ was potentiated by addition of the cytosolic fraction from control and IQ-treated rats, the latter being more effective. It was concluded that IQ, at the doses employed in the study, enhances its own bioactivation to genotoxic metabolites by stimulating both its microsomal and cytosolic metabolism. Several theoretical studies were performed with the aim to correlate physicochemical characteristics of HAAs with their carcinogenic properties [41,42]. In one of these studies [42], 11 possible 2-aminotrimethylimidazopyridine isomers were tested for mutagenic potency in the Ames/Salmonella test with bacterial strain TA98. These compounds are related to those found in heated muscle meats. Structural, quantum chemical, and hydropathic data were calculated on the parent molecules and the corresponding nitrenium ions. The principal determinants of higher mutagenic potency in these amines were indicated to be: (1) a small dipole moment, (2) the combination of b-face ring fusion and N3-methyl group, (3) a lower calculated energy of the p electron system, (4) a smaller energy gap between the amine HOMO and LUMO orbitals (Pearson ‘‘softness’’) (HOMO ¼ highest occupied molecular orbital, LUMO ¼ lowest unoccupied molecular orbital), and (5) a more stable nitrenium ion.
25.2.
REFERENCES
1. F. Toribio, R. Busquets, L. Puignou, M. T. Galceran, Food Chem. Toxicol., 45 (2007) 667. 2. T. Sugimura, T. Kawachi, M. Nagao, T. Yahagi, Y. Sano, T. Okamoto, K. Shudo, T. Kosuge, K. Tsuji, K. Wakabayashi, Y. Iitake, A. Itai, Proc. Japan Acad., 53B (1977) 58. 3. T. Yamamoto, K. Tsuji, T. Kosuge, T. Okamoto, K. Shudo, K. Takeda, Y. Iitake, K. Yamaguchi, Y. Seino, M. Nagao, T. Sugimura, Proc. Japan Acad., 54B (1978) 248. 4. J. F. C. Stavenuiter, M. Verrips-Kroon, E. J. Bos, J. G. Westra, Carcinogenesis, 6 (1985) 13. 5. S. Manabe, O. Wada, Y. Kanai, J. Environ. Sci. Health A, 26 (1991) 1449. 6. S. Manabe, O. Wada, Y. Kanai, J. Chromatogr., 529 (1990) 125. 7. S. Manabe, O. Wada, Environ. Pollut., 64 (1990) 121. 8. S. Kleinbauer, M. Rabache, Sci. Alim., 10 (1990) 417. 9. V. A. Basiuk, R. Navarro-Gonzalez, J. Chromatogr., 776 (1997) 255. 10. S. Manabe, K. Tohyama, O. Wada, T. Aramaki, Carcinogenesis, 12 (1991) 1945. 11. C. L. Holder, S. W. Preece, S. C. Conway, Y.-M. Pu, D. R. Doerge, Rapid Commun. Mass Spectrom., 11 (1998) 1667. 12. P. F. Britt, A. C. Buchanan Jr., C. V. Owens Jr., J. T. Skeen, Fuel, 83 (2004) 1417. 13. R. K. Sharma, W. G. Chan, M. R. Hajaligol, J. Anal. Appl. Pyrol., 75 (2006) 69. 14. Y. Kanai, O. Wada, S. Manabe, Carcinogenesis, 11 (1990) 1001. 15. R. K. Sharma, W. G. Chan, J. I. Seeman, M. R. Hajaligol, J. Anal. Appl. Pyrol., 66 (2003) 97. 16. D. Yoshida, T. Matsumoto, Cancer Lett., 10 (1980) 141. 17. T. Matsumoto, D. Yoshida, H. Tomita, Cancer Lett., 12 (1981) 105. 18. H. Kataoka, K. Kijima, G. Mauro, Bull. Environ. Contam. Toxicol., 60 (1998) 60. 19. T. A. Sasaki, J. M. Wilkins, J. B. Forehand, S. C. Moldoveanu, Anal. Lett., 34 (2001) 1749. 20. C. J. Smith, X. Qian, Q. Zha, S. C. Moldoveanu, J. Chromatogr. A, 1046 (2004) 211. 21. M. Yamashita, K. Wakabayashi, M. Nagao, S. Sato, Z. Yamaizumi, M. Takahashi, N. Kinae, I. Tomita, T. Sugimura, Japan J. Cancer Res., 77 (1986) 419. 22. K. Skog, Food Chem. Toxicol., 40 (2002) 1197. 23. T. Harraiz, Food Addit. Contam., 19 (2002) 748. 24. Y. Totsuka, H. Ushiyama, J. Ishihara, R. Sinha, S. Goto, T. Sugimura, K. Wakabayashi, Cancer Lett., 142 (1999) 139. 25. G. A. Gross, A. Gru¨ter, J. Chromatogr., 529 (1992) 271. 26. K. Skog, A. Solyakov, P. Arvidsson, M. Ja¨gerstad, J. Chromatogr. A, 803 (1998) 227. 27. F. Toribio, M. T. Galceran, L. Puignou, J. Chromatogr. B, 747 (2000) 171.
710
Pyrolysis of Organic Molecules
28. D. Kim, F. P. Guengrich, Annu. Rev. Pharmacol. Toxicol., 45 (2005) 27. 29. K. Wakabayashi, H. Ushiyama, M. Takahashi, H. Nukaya, S. B. -Kim, M. Hirose, M. Ochiai, T. Sugimura, M. Nagao, Environ. Health Prospect., 99 (1993) 129. 30. K. Wakabayashi, M. Nagao, H. Esumi, T. Sugimura, Cancer Res., 52 (1992) 2092. 31. T. Sugimura, Mutat. Res./Fund. Mol. Mech. Mutagen., 376 (1997) 211. 32. J. S. Felton, M. G. Knize, F. A. Dolbeare, R. Wu, Environ. Health Prospect. Suppl., 102 (1994) 201. 33. A. Hirata, T. Tsukamoto, H. Sakai, S. Takasu, H. Ban, T. Imai, Y. Totsuka, R. Nishigaki, K. Wakabayashi, T. Yanai, T. Masegi, M. Tatematsu, Food. Chem. Toxicol., 46 (2008) 2003. 34. P. Pias, M. G. Knize, J. Chromatogr. B, 747 (2000) 139. 35. H. Kataoka, J. Chromatogr. A, 774 (1997) 121. 36. M. Nagao, T. Sugimura, eds., Food Borne Carcinogens: Heterocyclic Amines, Wiley, New York, 2000. 37. T. Herraiz, J. Chromatogr. A, 881 (2000) 483. 38. J. Alexander, R. Reistad, S. Hegstad, H. Frandsen, K. Ingebritsen, J. E. Paulsen, G. Becher, Food. Chem. Toxicol., 40 (2002) 1131. 39. S. Sato, C. Negishi, A. Umemoto, T. Sugimura, Environ. Health Prospect., 67 (1986) 105. 40. A. D. Ayrton, E. J. Williams, A. D. Rodriguez, C. Ioannides, R. Walker, Mutagenesis, 4 (1989) 205. 41. G. L. Borosky, K. L. Laali, Org. Biomol. Chem., 3 (2005) 1180. 42. M. G. Knize, F. T. Hatch, M. J. Tanga, E. Y. Lau, M. E. Colvin, Environ. Mol. Mutagen., 47 (2005) 132.
CHAPTER 25
Toxicological Aspects of Aromatic Heterocyclic Amines 25.1.
HETEROCYCLIC AROMATIC AMINES
General aspects A number of heterocyclic aromatic amines (HAAs) are formed by pyrolytic processes particularly from amino acids in pure form, but also from amino acids and other nitrogenous compounds in interaction with sugars and creatinine. HAAs are also generated by pyrolysis from more complex mixtures containing nitrogenous materials like proteins, but without the possibility to determine the precise origin of the HAAs. Since HAAs are mutagenic and suspected carcinogens in humans, and because amino acids and sugars are common in food, the presence of HAAs in food is of particular concern. Some aspects regarding the formation of aromatic heterocyclic amines were discussed in Sections 13.5, 18.1, and 21.2. A considerable amount of information on the presence of HAAs in food, smoke, and environment is reported in the literature [1–31]. The information is also summarized in excellent reviews [27,32–35] and in at least one monograph [36]. Several studies were focused on mutagenic properties of HAAs [32]. These compounds are generated in food when it is cooked at temperatures over 150 1C. The range of HAAs levels is between 0.1 ppb and 50 ppb, depending on the food and cooking conditions. The HAAs are not only present in cooked red meat, fish, and chicken, but also at lower levels in baked and fried foods derived from grain. Mutagenicity of fried beef hamburgers cooked at 230 1C was determined to be 800737 TA98 revertants per gram of cooked material [32] in the Ames/Salmonella test. In the tested fried beef, the reported level of 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx) was 3.072.0 ng/g, of 2-amino-3,4, 8-trimethyl-imidazo[4,5-f]quinoxaline (DiMeIQx) was 1.070.18 ng/g, of 2-amino-3-methyl-imidazo[4,5f]quinoline (IQ) was 0.0670.03 ng/g, and of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was 9.6 ng/g. HAAs were capable of producing both reverse and forward mutations in Salmonella bacteria and forward mutations in Chinese hamster ovary cells (CHO). The number and type of mutations depended on the repair capacity of the cells for both Salmonella and CHO. Also, there were statistically significant increases in the mutations in the pancreas of the ‘‘mutamouse’’ following PhIP exposure. Based on findings from studies on multiple species of experimental animals it was shown that heterocyclic amines produced cancer in multiple organs including forestomach, cecum, colon, liver, oral cavity, Zymbal gland, mammary gland, and skin. Although evidence from human epidemiology suggests that consumption of well-done or grilled meat (which may contain HAAs) may be associated with increased cancer risk, the data are insufficient to support the conclusion that this risk is due specifically to certain HAAs present in these foods. The list of some heterocyclic amines (including two heterocyclic compounds, harman, and norharman) together with their most common origin is given in Table 25.1.1. The list of detected HAAs is not limited to those listed in Table 25.1.1. Other similar compounds, such as tetrahydro-b-carbolines [37] were reported in specific samples. Studies on HAAs were also directed toward the measuring of certain markers of exposure to these compounds [38]. For example, after ingestion by different animals, only a few percent of the initial levels of MeIQx and PhIP were excreted as parent compounds. It was determined that urinary levels of parent HAA reflect only recent exposure. The excreted glucuronide conjugates of N-hydroxy-PhIP and N-hydroxy-MeIQx could be markers for the N-hydroxylation capacity and HAA exposure. 5-OH-PhIP can be considered a metabolite marker for PhIP, since it is formed from this compound as a by-product along with the formation of PhIP-DNA adducts. PhIP also gives adducts of serum albumin and hemoglobin. In mice, PhIP is irreversibly incorporated in a dose-dependent manner into hair. In humans exposed to an ordinary diet it was found that the level of PhIP can vary from o50–5000 pg PhIP/g hair.
708
Pyrolysis of Organic Molecules
TABLE 25.1.1. Heterocyclic amines of health concern and their most likely source following pyrolysis Likely pyrolytic origin
Reference
Soybean globulin
1, 5, 6, 16, 19, 20
Acronym
Compound
AaC
2-Amino-9H-pyrido[2,3-b]indole
4-CH2OH-8-MeIQx
2-Amino4-hydroxymethyl-3,8-dimethylimidazo[4,5-f]quinoxaline
Cre-P-1
4-Amino-1,6-dimethyl-2-methylamino-1H,6Hpyrrolo[3,4-f]benzimidazol2-5,7-dione
Proteins
27
4,8-DiMeIQx
2-Amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline
Fried beef
27
7,8-DiMeIQx
2-Amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline
27
7,9-DiMeIgQx
2-Amino-1,7,9-trimethylimidazo[4,5-f]quinoxaline
27
16–18, 26
1,6-DMIP
2-Amino-1,6-dimethylimidazo[4,5-b]pyridine
Glu-P-1
2-Amino-6-methyldipyrido[1,2-a: 3u, 2u-d]imidazole
Glutamic acid
27
Glu-P-2
2-Aminodipyrido[1,2-a:3u2u-d]imidazole
Glutamic acid
10, 13–15
Harman
1-Methyl-9H-pyrido[3,4-b]indole
Coffee
20, 23, 24
IFP
2-Amino-1,6-dimethylfuro[3,2-e]imidazo[4,5-b]pyridine
IQ
2-Amino-3-methylimidazo[4,5-f]quinoline
Broiled sardines
10, 25
IQx
2-Amino-3-methylimidazo[4,5-f]quinoxaline
Lys-P-1
3,4-Cyclopentenopyrido[3,2-a]carbazole
Lysine
27
MeAaC
2-Amino-3-methyl-9H-pyrido[2,3-b]indole
Soybean globulin
1, 5, 6, 10, 16
10, 13–15, 18
22, 27 21, 28
MeIQ
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline
Broiled sardines
18
8-MeIQx
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline
Fried beef
1, 18, 22, 25, 26
4-MeIQx
2-Amino-3,4-dimethylimidazo[4,5-f]quinoxaline
Fried beef
1, 18, 22, 25, 26
1-Methyl-6-phenylimidazolo[4,5-b]pyridine-2-ylamine
Alanine?
27
Norharman
9H-Pyrido[3,4-b]indole
Coffee
13, 15, 20, 23, 24
Orn-P-1
4-Amino-6-methyl-1H-2,5,10,10b-tetraazafluoranthene
Ornithine
27
4uOH-PhIP
2-Amino-1-methyl-6-(4-hydroxyphenyl)imidazo[4,5b]pyridine
Phe-P-1
2-Amino-5-phenylpyridine
Phenylalanine
2, 27
PhIP
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Smoke
11, 19, 22, 25
1,5,6-TMIP
2-Amino-1,5,6-trimethylimidazo[4,5-b]pyridine
Trp-P-1
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole
Tryptophan
Trp-P-2
3-Amino-1-methyl-5H-pyrido[4,3-b]indole
Tryptophan
TriMeIQx
2-Amino-3,4,7,8-tetramethylimidazo[4,5-f]quinoxaline
27
27 1, 2, 5–7 2, 5–7, 10 27
It was suggested that this measurement could provide an indication of the level of exposure to PhIP [38]. Other studies attempted to find the metabolic path of HAAs [28,39]. It is likely that the first step in metabolic activation of mutagenic and carcinogenic heterocyclic amines is N-hydroxylation by cytochrome P-448. N-hydroxyamino compounds are further activated to form N-O-acyl derivatives that readily react with DNA. The adducts between the metabolites of Trp-P-2 and Glu-P-1, and DNA were shown to have a C8-guanylamino structure [39]. In the case of Glu-P-1, modification of guanine in GC clusters occurs preferentially. It was shown also that glutathione transferases and myeloperoxidase inactivated some heterocyclic amines or their active metabolites [39]. Also, hemin and fatty acids bind to HAAs and inactivate them. Fibers and other factors from vegetables also work to inactivate heterocyclic amines. Nitrite at low pH degraded some heterocyclic amines, but those with an imidazole moiety were found to be resistant. Glu-P-1 induced intestinal tumors in a high incidence when fed orally to rats.
Toxicological aspects of aromatic heterocyclic amines
709
When 14C-Glu-P-1 was administered by gavage into rats, about 50% and 35% were excreted into feces and urine, respectively, within 24 h. When the bile was collected, around 60% of radioactivity was found excreted into it within 24 h. In the bile, N-acetyl-Glu-P-1 was identified as one of the metabolites of Glu-P-1 [39]. In a different study [40], the metabolic activation of IQ to mutagenic intermediates in the Ames test was studied with hepatic activation systems from control and IQ-treated rats. Hepatic S9 preparations from IQ-treated rats were more efficient than the control in converting IQ to mutagens. An increase was seen also when isolated microsomes were employed as activation systems, but this was less pronounced. The microsome-mediated mutagenicity of IQ was potentiated by addition of the cytosolic fraction from control and IQ-treated rats, the latter being more effective. It was concluded that IQ, at the doses employed in the study, enhances its own bioactivation to genotoxic metabolites by stimulating both its microsomal and cytosolic metabolism. Several theoretical studies were performed with the aim to correlate physicochemical characteristics of HAAs with their carcinogenic properties [41,42]. In one of these studies [42], 11 possible 2-aminotrimethylimidazopyridine isomers were tested for mutagenic potency in the Ames/Salmonella test with bacterial strain TA98. These compounds are related to those found in heated muscle meats. Structural, quantum chemical, and hydropathic data were calculated on the parent molecules and the corresponding nitrenium ions. The principal determinants of higher mutagenic potency in these amines were indicated to be: (1) a small dipole moment, (2) the combination of b-face ring fusion and N3-methyl group, (3) a lower calculated energy of the p electron system, (4) a smaller energy gap between the amine HOMO and LUMO orbitals (Pearson ‘‘softness’’) (HOMO ¼ highest occupied molecular orbital, LUMO ¼ lowest unoccupied molecular orbital), and (5) a more stable nitrenium ion.
25.2.
REFERENCES
1. F. Toribio, R. Busquets, L. Puignou, M. T. Galceran, Food Chem. Toxicol., 45 (2007) 667. 2. T. Sugimura, T. Kawachi, M. Nagao, T. Yahagi, Y. Sano, T. Okamoto, K. Shudo, T. Kosuge, K. Tsuji, K. Wakabayashi, Y. Iitake, A. Itai, Proc. Japan Acad., 53B (1977) 58. 3. T. Yamamoto, K. Tsuji, T. Kosuge, T. Okamoto, K. Shudo, K. Takeda, Y. Iitake, K. Yamaguchi, Y. Seino, M. Nagao, T. Sugimura, Proc. Japan Acad., 54B (1978) 248. 4. J. F. C. Stavenuiter, M. Verrips-Kroon, E. J. Bos, J. G. Westra, Carcinogenesis, 6 (1985) 13. 5. S. Manabe, O. Wada, Y. Kanai, J. Environ. Sci. Health A, 26 (1991) 1449. 6. S. Manabe, O. Wada, Y. Kanai, J. Chromatogr., 529 (1990) 125. 7. S. Manabe, O. Wada, Environ. Pollut., 64 (1990) 121. 8. S. Kleinbauer, M. Rabache, Sci. Alim., 10 (1990) 417. 9. V. A. Basiuk, R. Navarro-Gonzalez, J. Chromatogr., 776 (1997) 255. 10. S. Manabe, K. Tohyama, O. Wada, T. Aramaki, Carcinogenesis, 12 (1991) 1945. 11. C. L. Holder, S. W. Preece, S. C. Conway, Y.-M. Pu, D. R. Doerge, Rapid Commun. Mass Spectrom., 11 (1998) 1667. 12. P. F. Britt, A. C. Buchanan Jr., C. V. Owens Jr., J. T. Skeen, Fuel, 83 (2004) 1417. 13. R. K. Sharma, W. G. Chan, M. R. Hajaligol, J. Anal. Appl. Pyrol., 75 (2006) 69. 14. Y. Kanai, O. Wada, S. Manabe, Carcinogenesis, 11 (1990) 1001. 15. R. K. Sharma, W. G. Chan, J. I. Seeman, M. R. Hajaligol, J. Anal. Appl. Pyrol., 66 (2003) 97. 16. D. Yoshida, T. Matsumoto, Cancer Lett., 10 (1980) 141. 17. T. Matsumoto, D. Yoshida, H. Tomita, Cancer Lett., 12 (1981) 105. 18. H. Kataoka, K. Kijima, G. Mauro, Bull. Environ. Contam. Toxicol., 60 (1998) 60. 19. T. A. Sasaki, J. M. Wilkins, J. B. Forehand, S. C. Moldoveanu, Anal. Lett., 34 (2001) 1749. 20. C. J. Smith, X. Qian, Q. Zha, S. C. Moldoveanu, J. Chromatogr. A, 1046 (2004) 211. 21. M. Yamashita, K. Wakabayashi, M. Nagao, S. Sato, Z. Yamaizumi, M. Takahashi, N. Kinae, I. Tomita, T. Sugimura, Japan J. Cancer Res., 77 (1986) 419. 22. K. Skog, Food Chem. Toxicol., 40 (2002) 1197. 23. T. Harraiz, Food Addit. Contam., 19 (2002) 748. 24. Y. Totsuka, H. Ushiyama, J. Ishihara, R. Sinha, S. Goto, T. Sugimura, K. Wakabayashi, Cancer Lett., 142 (1999) 139. 25. G. A. Gross, A. Gru¨ter, J. Chromatogr., 529 (1992) 271. 26. K. Skog, A. Solyakov, P. Arvidsson, M. Ja¨gerstad, J. Chromatogr. A, 803 (1998) 227. 27. F. Toribio, M. T. Galceran, L. Puignou, J. Chromatogr. B, 747 (2000) 171.
710
Pyrolysis of Organic Molecules
28. D. Kim, F. P. Guengrich, Annu. Rev. Pharmacol. Toxicol., 45 (2005) 27. 29. K. Wakabayashi, H. Ushiyama, M. Takahashi, H. Nukaya, S. B. -Kim, M. Hirose, M. Ochiai, T. Sugimura, M. Nagao, Environ. Health Prospect., 99 (1993) 129. 30. K. Wakabayashi, M. Nagao, H. Esumi, T. Sugimura, Cancer Res., 52 (1992) 2092. 31. T. Sugimura, Mutat. Res./Fund. Mol. Mech. Mutagen., 376 (1997) 211. 32. J. S. Felton, M. G. Knize, F. A. Dolbeare, R. Wu, Environ. Health Prospect. Suppl., 102 (1994) 201. 33. A. Hirata, T. Tsukamoto, H. Sakai, S. Takasu, H. Ban, T. Imai, Y. Totsuka, R. Nishigaki, K. Wakabayashi, T. Yanai, T. Masegi, M. Tatematsu, Food. Chem. Toxicol., 46 (2008) 2003. 34. P. Pias, M. G. Knize, J. Chromatogr. B, 747 (2000) 139. 35. H. Kataoka, J. Chromatogr. A, 774 (1997) 121. 36. M. Nagao, T. Sugimura, eds., Food Borne Carcinogens: Heterocyclic Amines, Wiley, New York, 2000. 37. T. Herraiz, J. Chromatogr. A, 881 (2000) 483. 38. J. Alexander, R. Reistad, S. Hegstad, H. Frandsen, K. Ingebritsen, J. E. Paulsen, G. Becher, Food. Chem. Toxicol., 40 (2002) 1131. 39. S. Sato, C. Negishi, A. Umemoto, T. Sugimura, Environ. Health Prospect., 67 (1986) 105. 40. A. D. Ayrton, E. J. Williams, A. D. Rodriguez, C. Ioannides, R. Walker, Mutagenesis, 4 (1989) 205. 41. G. L. Borosky, K. L. Laali, Org. Biomol. Chem., 3 (2005) 1180. 42. M. G. Knize, F. T. Hatch, M. J. Tanga, E. Y. Lau, M. E. Colvin, Environ. Mol. Mutagen., 47 (2005) 132.