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Food-Derived Mutagens and Carcinogens1

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Food-Derived Mutagens and Carcinogens1 [CANCER RESEARCH (SL'PPL.) 52. 2092s-2098s. April I, 1992] Food-derived Mutagens and Carcinogens1 Keiji Wakabayashi,2 Minako Nagao, Hiroyasu Esumi, and Takashi Sugimura National Cancer Center Research Institute, l-l, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan Abstract pounds have planar structures that can be inserted between the base pairs of double-stranded DNA. Charred parts of broiled Cooked food contains a variety of mutagenic heterocyclic amines. All the mutagenic heterocyclic amines tested were carcinogenic in rodents fish and meat were also found to be mutagenic to TA98 after when given in the diet at 0.01-0.08%. Most of them induced cancer in metabolic activation (9, 10). These findings led to the isolations the liver and in other organs. It is noteworthy that the most abundant of the mutagenic compounds, IQ,' MelQ, MelQx from broiled heterocyclic amine in cooked food, 2-amino-l-methyl-6-phenylimi- fish and meat (5-7). Later PhIP was also isolated as member dazo(4,5-A|pyridine, produced colon and mammary carcinomas of this class of mutagens (11). These heterocyclic amines were in rats and lymphomas in mice but no hepatomas in either. 2-Amino-3- methylimidazo(4,5-/]quinoline induced liver cancer in monkeys. Forma formed by heating mixtures of creatinine, sugars, and amino acids, which are present in raw meat and fish (12-16). More tion of adducts with guanine by heterocyclic amines is presumably involved in their carcinogenesis. Quantification of heterocyclic amines in recently identified mutagens have been found to contain oxygen cooked foods and in human urine indicated that humans are continuously atoms (17-19). Before the discoveries of imidazoquinoline and exposed to low levels of them in the diet. These low levels of heterocyclic imidazoquinoxaline compounds, pyrolysates of food compo amines are probably insufficient to produce human cancers by themselves. nents, amino acids, and proteins were shown to contain muta However, a linear relationship between DNA adduct levels and a wide genic substances. These findings led to the identification of range of doses of a heterocyclic amine was demonstrated in animals. It pyridoindole, dipyridoimidazole, phenylpyridine, and tetraaza- suggests that even very low doses of heterocyclic amines form DNA adducts and may be implicated in the development of human cancer under fluoranthene derivatives as new mutagenic heterocyclic amines conditions in which many other mutagens-carcinogens, tumor promoters, in pyrolysates of amino acids and of amino-a-carboline deriva and factors stimulating cancer progression exist. tives as mutagenic compounds in a pyrolysate of protein (4-7). Some of the heterocyclic amines that were originally isolated Introduction from pyrolysates of amino acids and proteins were also re covered from cooked foods (6). Diet plays an important role in cancer development: high intakes of total calories and fat enhance cancer development, excessive intake of sodium chloride promotes carcinogenesis in Chemistryof Heterocyclic Amines in Foods the stomach, whereas, in contrast, fiber, carotene, and vitamins protect against cancer development (1, 2). Foods also contain The heterocyclic amines reported so far are listed in Table 1 mutagenic and/or carcinogenic substances as very minor com with their chemical names, abbreviations, and sources (11, 17, ponents: mycotoxin contaminants, nitrosamines, polycyclic ar 18, 20-29). They are classified as IQ-type compounds, in which omatic hydrocarbons, and plant alkaloids (3). the amino group is not changed by treatment with 2 HIMsodium A series of mutagenic-carcinogenic substances have been nitrite, and as non-IQ-type compounds, in which the amino found in cooked meat and fish in the last 15 years. New group is converted to a hydroxy group with 2 HIMsodium nitrite heterocyclic amine compounds were isolated by monitoring the (30). The amino group of IQ-type heterocyclic amines is con fractionation and purification of mutagens by using microbial verted to a nitro group with 50 mM sodium nitrite and the mutation assays (4-7). These compounds have much higher mutagenic activity than other typical mutagens-carcinogens and resulting compound shows a similar mutagenicity to the origi nal compound in the absence of S9 mix (31). Most of these were later shown to be carcinogenic in rodents and nonhuman heterocyclic amines have been synthesized in large quantities primates. This review deals mainly with mutagenic and carcin for use in long-term experiments in rodents (6, 32). These ogenic heterocyclic amines that are produced under ordinary cooking conditions. compounds remain stable in experimental diets if these diets In 1939, Widmark (8) reported that organic solvent extracts are kept cold and dry. They are also sufficiently stable in dilute of broiled horse meat induced tumors in mammary glands when aqueous solution for biological experiments. repeatedly painted on the backs of mice. In the 1970s we became The structures of heterocyclic amines are shown in Fig. 1. A interested in whether the smoke produced by broiling meat and heterocyclic amine containing oxygen, namely aminomethylim- fish contained mutagenic and carcinogenic activity, because idazofuropyridine, can exist as four possible isomers because cigarette smoke condensate was known to contain many muta there are two possible positions for both the oxygen and N- gens-carcinogens. We found that a smoke condensate obtained methyl group (17). A mutagenic heterocyclic amine containing by broiling fish and trapping the smoke on glass fiber filters oxygen atoms was also isolated from a creatine pyrolysate and exerted mutagenic activity toward Salmonella typhimurium identified as Cre-P-1 (Fig. 1) (18). However, the presence of TA98 after microsomal metabolic activation (9, 10). TA98 was Cre-P-1 in cooked food has not yet been reported. more sensitive than TA 100, indicating that the mutagenic com- 3The abbreviations used are: IQ. 2-amino-3-methylimidazo[4,5-/)quinoline; 1Presented at "Nutrition and Cancer," the first conference of the International MelQ. 2-amino-3.4-dimethylimidazo[4,5-/]quinoline; MelQx, 2-amino-3,8-di- Conference Series on Nutrition and Health Promotion. April 17-19. 1991. methylimidazo|4,5-/|quinoxaline; PhIP, 2-amino-1 -methyl-o-phenylimidazo^.S- Atlanta, GA. This study was supported by Grams-in-Aid for Cancer Research Ajpyridine; AnC. 2-amino-9//-pyrido[2,3-ft]indole; MeAaC, 2-amino-3-methyl- from the Ministry of Health and Welfare and the Ministry of Education. Science 9//-pyrido[2,3-6]indole; Trp-P-2.3-amino-1 -methyl-5//-pyrido|4,5-e]indole; Glu- and Culture of Japan, and a Grant-in-Aid from the Ministry of Health and P-1. 2-amino-6-methyldipyrido(1,2-a:3',2'-</]imidazole; Cre-P-1,4-amino-1,6-di- Welfare for a Comprehensive 10-Year Strategy for Cancer Control, Japan. methyl-2-methylamino-l//.6//-pyrrolo[3.4-/]benzimidazole-5,7-dione; Trp-P-I, ; To whom requests for reprints should be addressed. 3-amino-1,4-dimethyl-5//-pyrido|4,3-ojindole. 2092s Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1992 American Association for Cancer Research. FOOD-DERIVED Ml'TAGENS AND CARCINOGENS Table 1 Chemical names, abbreviations, and sources of isolated helerocyclic amines and references name2-Amino-3-methylimidazo[4.5-/]quinoline2-Amino-3,4-dimethylimidazo|4.5-/)quinoline2-Amino-3-methylimidazo|4,5-./]quinoxaline2-Amino-3.8-dimethylimidazo[4.5-/]quinoxaline2-Amino-3,4,8-trimelhylimidazo[4,5,-./]quinoxaline2-Amino-3.7,8-trimethylimidazo[4,5-/)quinoxaline2-Amino-Chemical sardineBroiledsun-dried sardineCreatine-supplememedsun-dried friedNorwegian productFried meat beefHeated creatinine.threonine.mixture of glucoseHeatedand creatinine.glycine,mixture of glucoseFriedand -methyl-o-phenylimidazo^.S-Alpyridine2-Amino-n.n.n-trimethylimidazopyridine2-Amino-n.n-dimelhylimidazopyridine2-Amino-(l1 beefCreatine-supplcmented friedNorwegian productCreatine-supplementedmeat friedNorwegian productFried meat 3,2)-e|imi-dazo[4.5-ft]p>or 3).6-dimelhylfuro[2.3(or mixture of beef, crea ridine4-Amino- milkCreatinetine, and W.6W-pyr-rolo[3.4-/)benzimidazole-5.7-dione3-Amino-1,6-dimethyl-2-methylamino- 1 pyrolysateTryptophan ,4-dimethyl-5//-pyrido[4.3-6]indole3-Amino-1 pyrolysateTryptophan -methyl-5//-pyrido(4,3-o]indole2-Amino-6-methyldipyrido[l,2-a:3'.2'-</]imidazole2-Aminodipyrido|l,2-a:3'.21 pyrolysateGlutamic pyrolysateGlutamicacid -rf]imidazole2-Amino-5-phenylpyridine4-Amino-6-methyl- pyrolysatePhenylalanineacid pyrolysateOrnithine 06-tetraazafluoranthene2-Amino-9//-pyrido|2,3-A]indole2-Amino-3-methyl-9//-pyrido[2,3-*]indoleAbbreviationIQMelQIQxMelQx4,8-DiMeIQx7,8-DiMeIQxPhIPTMIPDMIPMelFPCre-P-1Trp-P-1Trp-P-2Glu-P-1Glu-P-2Phe-P-1Orn-P-1AaCMeAaCSourceBroiled1H-2, 5, 10, 1 pyrolysateSoybean pyrolysateSoybeanglobulin globulin pyrolysateReference202122232425II222217182626272726282929 Mutagenesis gland cancers in female rats (47), and lymphomas in mice of both sexes (48). As described briefly in the introduction, heterocyclic amines Injection s.c. of Trp-P-1 resulted in the formation of fibro- are more mutagenic toward 5. typhimurium TA98 than TA 100. sarcomas at the injection site in F344 rats and Syrian golden The specific mutagenicities of some heterocyclic amines are hamsters (54). Intragastric intubation of IQ resulted in devel much stronger than those of typical mutagens-carcinogens such opment of tumors in the mammary gland, liver, and ear duct as aflatoxin B,, 4-nitroquinoline 1-oxide, and benzo[a]pyrene. of SD rats (55). Intestinal tumors developed much more rapidly
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