MUTAGENS RESULTING FROM COOKING OF FOODS

Mutagens from Pyrolyzed Proteins and Amino Acids

During the past few years, it has become clear that PAH's account for only a small fraction of the mutagenic (and, therefore, potentially carcinogenic) activity that occurs in foods during cooking. Nagao et al. (1977a) used dimethylsulfoxide to prepare extracts of the charred surfaces of broiled fish and meat. They found that the mutagenic activities of these extracts for histidine-requiring strains of S. typhimurium were hundreds or thousands of times greater than could be accounted for by the reported benzo[a]pyrene contents of these cooked foods. For example, the mutagenic activity of charcoal-broiled beefsteak was the equivalent to that of approximately 4,500 μg of benzo[a]-pyrene per kilogram of steak, even though Lijinsky and Shubik (1964) had reported that charcoal-broiled steak contained no more than 8 μg of this chemical per kilogram.

The mutagenic activity in the broiled fish and beef could also be detected in S. typhimurium strain TA98, implying that the agent could induce frameshift mutations (Nagao et al., 1977a; Sugimura et al., 1977). Positive results in these assays depended on the presence of an in vitro metabolic activation system utilizing the postmitochondrial supernatant from homogenized livers of rats pretreated with polychlorinated biphenyls. Bjeldanes et al. (in press, a, b) have recently completed a series of detailed studies on the cooking conditions under which mutagenic activity is produced in various types of fish, meats (including organ meats), as well as eggs, milk, cheese, and tofu.

To determine what constituent or constituents of fish and meat contribute to the mutagenic activity produced by cooking, studies have been conducted to examine the mutagenicity of smoke condensates from various substances. Smoke obtained from pyrolyzed proteins, such as lysozyme and histone, was found to be highly mutagenic to S. typhimurium, whereas smoke condensates from pyrolyzed DNA, RNA, starch, or vegetable oil were only slightly mutagenic (Nagao et al., 1977b). Pyrolysis of tryptophan resulted in more mutagenic activity than did any other common amino acid, but almost all of the amino acids tested yielded some mutagenic activity when pyrolyzed (Matsumoto et al., 1977; Nagao et al., 1977c).

Purification of the mutagenic products resulting from pyrolysis of tryptophan resulted in the isolation of two previously unknown amino-γ-carbolines that are potent mutagens: 3-amino-l,4,-dimethyl-5H-pyrido-[4,3-b]indole (referred to as Trp-P-1, for “Tryptophan Pyrolysate 1”) and 3-amino-1-methyl-5H-pyrido[4, 3-b]indole (Trp-P-2) (Akimoto et al., 1977; Sugimura et al., 1977; Takeda et al., 1977).

The mutagenic activity resulting from pyrolysis of L-glutamic acid was shown to be due to the formation of 2-amino-6-methyldipyrido-[1, 2-a:3'2'-d]imidazole (Glu-P-1) and 2-aminodipyrido[1, 2-a:3',2'-d]-imidazole (Glu-P-2) (Yamamoto et al., 1978). The structural similarity between these products of glutamic acid pyrolysate and Trp-P-1 and Trp-P-2 is evident from Figure 13-1.

FIGURE 13-1.

Some mutagens from pyrolysates and from cooked foods.

Wakabayashi et al. (1978) isolated a different, but structurally related, heterocyclic mutagen from pyrolyzed lysine. This compound was 3,4-cyclopentenopyrido[3,2-a]carbazole (Lys-P-1). Pyrolysis of phenylalanine resulted in the formation of the mutagen 2-amino-5-phenylpyridine (Phe-P-1) (Sugimura et al., 1977).

When soybean globulin was pyrolyzed, the substances that contributed to the mutagenic activity were compounds not previously identified as pyrolysis products of any individual amino acid. These compounds, 2-amino-9H-pyrido[2, 3-b]indole (AαC) and 2-amino-3-methyl-9H-pyrido-[2, 3-b]indole (MeAαC), are quite closely related to the γ-carboline compounds Trp-P-1 and Trp-P-2 (Yoshida et al., 1978).

Uyeta et al. (1979) found that both Trp-P-1 and Trp-P-2 were present in pyrolysates of casein and gluten. Yamaguchi et al. (1979) identified Glu-P-2 in the tar resulting from pyrolysis of casein. These investigators estimated that Glu-P-2 and Glu-P-1 accounted for approximately 10% of the total mutagenic activity of the pyrolysate.

Analyses have confirmed that at least some of the mutagenic pyrolysis products of amino acids are present in cooked foods. For example, Trp-P-1 has been found in “very well done” broiled beef and Glu-P-2 in broiled cuttlefish, although they account for less than 10% of the total mutagenic activity in extracts of these foods (Yamaguchi et al., 1980a, b). Similarly, sardines broiled to a dark brown color contain Trp-P-1, Trp-P-2, and Phe-P-1, although most of the mutagenic activity in these fish was due to the presence of other compounds (Yamaizumi et al., 1980) (Table 13-1). Pieces of beef or chicken grilled in a high gas flame contained AαC and MeAαC (Matsumoto et al., 1981). Similarly, AαC could be identified in grilled onions.

TABLE 13-1

Mutagenic Activities of the Mutagens Isolated from Cooked Foods.

Two previously unknown mutagens were isolated from broiled sardines (Kasai et al., 1979). These were 2-amino-3-methylimidazo[4, 5-f]quinoline (IQ) and 2-amino-3, 4-dimethylimidazo[4, 5-f]quinoline (MeIQ), which are extraordinarily potent mutagens to S. typhimurium strain TA98 (Kasai et al., 1980a, b, c). Except for the beef that contained IQ and possibly that containing MeIQ and 2-amino-3, 8-dimethylimidazo-[4, 5-f]-quinoxaline (MeIQx), the foods listed as sources of mutagens in Table 13-1appear to have been very well cooked and even charred on the surfaces to produce the mutagenic compounds identified in the table. Information on mutagens formed by cooking foods at lower temperatures is discussed in the next section.

As discussed in Chapter 3, the mutagenic activity of a chemical in bacteria indicates potential genotoxicity and possible carcinogenicity in mammals. To test for carcinogenic activity, it is necessary to use mammalian cell systems and intact mammals. Whenever other test systems also indicate genotoxic activity, it is more likely that a bacterial mutagen can act as a carcinogen.

Four of the mutagenic pyrolysates derived from amino acids or protein--Trp-P-1, Trp-P-2, Glu-P-1, and AαC--have been shown to induce sister chromatid exchanges in a permanent line of human lymphoblastoid cells (Tohda et al., 1980). In addition, the basic fraction extracted from pyrolyzed tryptophan was found to cause mutations resulting in resistance to ouabain or 8-azaguanine in cultured Chinese hamster lung cells (Inui et al., 1980). Trp-P-1, Trp-P-2, and GluP-1 can transform primary Syrian golden hamster embryo cells (Takayama et al., 1977, 1979). The cells transformed by Trp-P-2 have been shown to grow in soft agar and to result in tumors when inoculated into the cheek pouches of young hamsters with unimpaired immunocompetence (Takayama et al., 1978). Although these findings support the potential carcinogenicity of these chemicals, a definitive determination of carcinogenicity must be made in whole animals.

Several of the mutagenic pyrolysates of amino acids or proteins have been tested for carcinogenicity in vivo. Neoplastic nodules, which are presumed to be precancerous changes, were found in the livers of Wistar rats given the basic fraction from pyrolyzed tryptophan at 0.2% in the diet (Matsukura et al., 1981b). Neither neoplastic nodules nor liver tumors had previously been observed in this strain of rats in this laboratory. Subcutaneous injection of Trp-P-1 (1.5 mg once a week for 20 weeks) induced sarcomas in Syrian golden hamsters and in Fischer rats (Ishikawa et al., 1979). Trp-P-2 did not induce tumors in either hamsters or rats under the same experimental conditions (Ishikawa et al., 1979). Trp-P-1 and Trp-P-2 produced liver tumors in CDF₁ (BALB/c × DBA) mice that were fed a diet containing 0.02% of either of these chemicals (Matsukura et al., 1981a). Some of these liver tumors metastasized to the lung. Female mice were more susceptible to these carcinogens than were the males. Six of nine female ACI rats fed 0.1% Trp-P-2 in their diet developed neoplastic nodules of the liver, and one of the six developed a hemangioendothelial sarcoma of the liver (Hosaka et al., 1981). None of the control animals developed such nodules or tumors. Glu-P-1, Glu-P-2, AαC, and MeAαC induced hepatomas in mice. Glu-P-1 and Glu-P-2 also induced hemangioendotheliomas between the scapulae of mice fed diets containing 0.05% of either of these chemicals (Sugimura, in press). Thus, it appears that the identification of several of the mutagenic compounds found in pyrolysates of proteins and amino acids was an accurate predictor of carcinogenicity. However, the presence of a carcinogenic chemical in a pyrolyzed amino acid or protein mixture does not necessarily imply that the carcinogen will also be present in normally cooked, uncharred food.

PLANT FLAVONOIDS

Among the most widespread of the known naturally occurring mutagens (possible carcinogens) that are normal constituents of many foods are the mutagenic flavonoids. Among the flavonol aglycones that have been shown to be mutagenic to S. typhimurium are quercetin, kaempferol, and galangin (Bjeldanes and Chang, 1977; Brown, 1980; Hardigree and Epler, 1978; MacGregor and Jurd, 1978). Quercetin has also been reported to induce gene conversion in yeast (Hardigree and Epler, 1978), transformation of both hamster embryo cells (Umezawa et al., 1977) and BALB/c 3T3 mouse cells (Meltz and MacGregor, 1981), and mutations and single-stranded DNA breaks in L5178Y mouse cells (Meltz and MacGregor, 1981). Both quercetin and kaempferol have been reported to cause mutations in V79 Chinese hamster cells (Maruta et al., 1979) and heritable mutations (sex-linked recessive lethals) in the fruit fly Drosophila melanogaster (Watson, 1982).

In some mutagenic plant products consumed by humans, the mutagenic substances isolated were identified as flavonoids. For example, most of the mutagenic activity of an acid hydrolysate of green tea could be accounted for by three flavonoids: kaempferol, quercetin, and myricetin (Uyeta et al., 1981). The flavonoids kaempferol and isorhamnetin were found to be responsible for most of the mutagenic activity found in Japanese pickles (Takahashi et al., 1979). The mutagen in the spice of sumac was found to be quercetin (Seino et al., 1978). Isorhamnetin and quercetin were the major mutagens in a methanol extract of dill weed (Fukouka et al., 1980).

Brown (1980) reported that the edible portions of most food plants contain flavonoid glycosides, especially quercetin and kaempferol. He estimated that the average daily intake of flavonoids in the U.S. diet is approximately 1 g and that the daily intake of mutagenic flavonoid glycosides may be equivalent to approximately 50 mg of quercetin. Approximately 25% of the flavonoid intake is derived from tea, coffee, cocoa, fruit jams, red wine, beer, and vinegar (Brown, 1980).

In view of the mutagenic activity and widespread distribution of certain flavonoids, particularly quercetin, it is important to determine the carcinogenic potential of these chemicals. At present, the data concerning the carcinogenicity of quercetin are contradictory. Pamukcu et al. (1980) reported that adding 0.1% quercetin to the diet of albino Norwegian rats for 58 weeks resulted in the induction of tumors in the epithelium of the intestine and urinary bladder. However, when Saito et al. (1980) fed 2% quercetin to ddY mice throughout the lives of the animals, they found no significant increase in tumor incidence. At doses as high as 10% quercetin in the diet fed throughout life, no significant increase in tumor incidence was observed in ACI rats (Hirono et al., 1981) or in hamsters (Morino et al., 1982). The reason for the discrepancy between the findings of Pamukcu et al. and the other investigators is not clear, but may relate to differences in sensitivity among the species and strain tested.

Flavonols often exist in plants in the form of glycosides. For example, rutin is a glycoside of quercetin that can be hydrolyzed to release quercetin by enzymatic or chemical treatment. Such hydrolysis, mediated by intestinal bacteria, occurs when glycosides are consumed in foods. Rutin and other glycosides of mutagenic flavonoids have been shown to be mutagenic to S. typhimurium following treatment with glycosidase-containing extracts of the mold Aspergillus niger (Nagao et al., 1981), the snail Helix pomatia (Brown and Dietrich, 1979), rat cecal contents (Brown and Dietrich, 1979), or human feces (Tamura et al., 1980). Mutagenic activity of rutin has also been reported in S. typhimurium in the absence of glycosidase treatment, but only at doses higher than those required when such treatment is used (Hardigree and Epler, 1978).

MUTAGENIC ACTIVITY IN EXTRACTS OF FOODS AND BEVERAGES

Several food substances have been reported to contain mutagenic activity, although the specific chemicals responsible for this activity have not yet been identified. For example, coffee is mutagenic to Salmonella typhimurium strain TA100, whether it is brewed, instant, or decaffeinated (Aeschbacher and Würzner, 1980; Aeschbacher et al., 1980; Nagao et al., 1979). Although caffeine has been reported to be mutagenic to bacteria (Clarke and Wade, 1975; Demerec et al., 1948, 1951; Gezelius and Fries, 1952; Glass and Novick, 1959; Johnson and Bach, 1965; Kubitschek and Bendigkeit, 1958, 1964; Novick, 1956), it could not have been responsible for the mutagenicity of coffee observed in these reports, since decaffeinated coffee was as mutagenic as regular coffee and caffeine itself was not detected as a mutagen under the test conditions used (Aeschbacher et al., 1980; Nagao et al., 1979). Studies examining the possible carcinogenicity of coffee are discussed in Chapter 12.

Black tea, green tea, and roasted tea were mutagenic to S. typhimurium strain TA100 in the absence of added enzymes (Nagao et al., 1979).When extracts of Aspergillus niger or human feces containing enzymes capable of hydrolyzing glycosides were added, tea became mutagenic to S. typhimurium strain TA98 (Nagao et al., 1979; Tamura et al., 1980). Acid hydrolysis of green or black tea also caused mutagenic activity to be released (Uyeta et al., 1981). The flavonols quercetin, kaempferol, and myricetin have recently been shown to account for most of the mutagenic activity of an acid hydrolysate of green tea (Uyeta et al., 1981). Grape juice was also found to be mutagenic to strain TA98, although only when tested with fecal extracts containing glycosidases (Tamura et al., 1980).

Mutagenic activity has also been detected in concentrates of 17 out of 27 commonly consumed Chinese alcoholic beverages, mostly fermented from rice, glutinous rice, and barley (Lee and Fong, 1979). The mutagenic spirits were those that had been distilled only once or to which herbs or meat had been added. Evaporated residues from 12 out of 13 Japanese, Scotch, and North American whiskies were found to contain mutagenic activity (Nagao et al., 1981). This activity did not require the addition of glycosidases or mammalian enzymes. It was mutagenic to S. typhimurium strain TA100, but not to TA98, indicating that it was inducing base-pair substitution rather than frameshift mutations. Some French brandies and apple brandies were also mutagenic when concentrated or fractionated (Loquet et al., 1981; Nagao et al., 1981).

Extracts of relatively few fruits, vegetables, and beverages are mutagenic. When Stoltz et al. (in press, a,b) fractionated extracts of 28 beverages and 40 fruits and vegetables, only 3 beverages and 5 fruits and vegetables showed reproducible mutagenic activity. The activity of three of the fruits (strawberries, raspberries, and peaches) was due to residues of the fungicide captan. Quercetin accounted for the mutagenicity of the remaining fruit and vegetable (raisins and onions) as well as two of the beverages (red wine and grape juice). The mutagen in coffee was not identified. This extensive survey of fractionated extracts of 68 foods did not reveal the presence of any mutagenic chemicals or foods that had not been previously reported. Similarly, Bjeldanes et al. (in press, a,b) found no significant mutagenic activity in extracts of eggs, milk, cheese, or tofu unless they had been cooked at high temperatures or to the point of darkening. Thus, with the exception of mutagens produced by cooking, it seems unlikely that large numbers of mutagens remain to be discovered in common foods.

MODIFIERS OF MUTAGENIC ACTIVITY

A number of substances in food have been reported either to enhance or to diminish the mutagenic activity of other substances. Most of these effects have been observed in in vitro test systems, and their relevance to effects in intact mammals is unknown. Modifiers of mutagenicity can be either comutagens or antimutagens. A comutagen is a substance that enhances the mutagenic activity of a chemical although it is not in itself mutagenic. This enhancement may take one of two forms: it may strengthen the mutagenic response of chemicals that are themselves mutagenic or may create a mutagenic response from nonmutagens. Similarly, an antimutagen is a substance that reduces or eliminates the mutagenic activity of a mutagen.

SUMMARY AND CONCLUSIONS

Considerable attention has recently been directed toward the presence of mutagenic activity in foods. Many vegetables contain mutagenic flavonoids such as quercetin, kaempferol, and their glycosides. Furthermore, some substances found in foods can enhance or inhibit the mutagenic activity of other compounds. Mutagens in charred meat and fish are produced during the pyrolysis of proteins that occurs when foods are cooked at very high temperatures. Normal cooking of meat at lower temperatures can also result in the production of mutagens. Smoking of foods as well as charcoal broiling results in the deposition of mutagenic and carcinogenic polynuclear aromatic compounds such as benzo[a]pyrene on the surface of the food.

The production of mutations in bacterial or other tests is an indication that a chemical may be carcinogenic in animals. However, many mutagens detected in foods have not been adequately tested for carcinogenicity. Of those that have been tested, the data on the carcinogenicity of the mutagenic flavonol quercetin are conflicting, and several mutagens isolated from pyrolyzed proteins or amino acids appear to be carcinogenic. It is not yet clear to what extent the mutagens produced by pyrolyzing proteins or amino acids are found in normally cooked foods. The finding that some constituents of food can enhance or inhibit the in vitro mutagenicity of other compounds should not be interpreted as meaning that these compounds would produce the same effects in living animals or humans.

If mutagens that are widely distributed in common foods are consistently found to cause cancer in animals, many factors should be considered before action is taken to reduce exposure. For example, cooking of meat and fish produces mutagens, but it also destroys pathogenic microorganisms and parasites. Furthermore, some foods contain mutagenic flavonoids but also have high nutritional value.

REFERENCES

• Aeschbacher, H. U., and H. P. Würzner. 1980. An evaluation of instant and regular coffee in the Ames mutagenicity test. Toxicol. Lett. 5:139-145. [PubMed: 7008262]
• Aeschbacher, H. U., C. Chappuis, and H. P. Würzner. 1980. Mutagenicity testing of coffee: A study of problems encountered with the Ames Salmonella test system. Food Cosmet. Toxicol. 18:605-613. [PubMed: 7009349]
• Akimoto, H., A. Kawai, H. Nomura, M. Nagao, T. Kawachi, and T. Sugimura. 1977. Syntheses of potent mutagens in tryptophan pyrolysates. Chem. Lett. 9:1061-1064.
• Arimoto, S., T. Negishi, and H. Hayatsu. 1980. a. Inhibitory effect of hemin on the mutagenic activities of carcinogens. Cancer Lett. 11:29-33. [PubMed: 7226136]
• Arimoto, S., Y. Ohara, T. Namba, T. Negishi, and H. Hayatsu. 1980. b. Inhibition of the mutagenicity of amino acid pyrolysis products by hemin and other biological pyrrole pigments. Biochem. Biophys. Res. Commun. 92:662-668. [PubMed: 6986874]
• Baird, M. B., and L. S. Birnbaum. 1979. Inhibition of 2-fluorenamine-induced mutagenesis in Salmonella typhimurium by vitamin A. J. Natl. Cancer Inst. 63:1093-1096. [PubMed: 384006]
• Bjeldanes, L. F., and G. W. Chang. 1977. Mutagenic activity of quercetin and related compounds. Science 197:577-578. [PubMed: 327550]
• Bjeldanes, L. F., M. M. Morris, J. S. Felton, S. Healy, D. Stuermer, P. Berry, H. Timourian, and F. T. Hatch. In press a. Mutagens from the cooking of food. II. Survey by Ames/Salmonella test of mutagen formation in the major protein-rich foods of the American diet. Food Chem. Toxicol. [PubMed: 6751953]
• Bjeldanes, L. F., M. M. Morris, J. S. Felton, S. Healy, D. Stuermer, P. Berry, H. Timourian, and F. T. Hatch. In press b. Mutagens from the cooking of food. III. Secondary sources of cooked dietary protein. Food Chem. Toxicol. [PubMed: 6751954]
• Brown, J. P. 1980. A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds. Mutat. Res. 75:243-277. [PubMed: 6770263]
• Brown, J. P., and P. S. Dietrich. 1979. Mutagenicity of plant flavonols in the Salmonella/mammalian microsome test. Activation of flavonol glycosides by mixed glycosidases from rat cecal bacteria and other sources. Mutat. Res. 66:223-240. [PubMed: 375081]
• Busk, L., and U. G. Ahlborg. 1980. Retinol (vitamin A) as an inhibitor of the mutagenicity of aflatoxin B ₁. Toxicol. Lett. 6:243-249. [PubMed: 6999664]
• Clarke, C. H., and M. J. Wade. 1975. Evidence that caffeine, 8-methoxy-psoralen and steroidal diamines are frameshift mutagens for E. coli K-12. Mutat. Res. 28:123-125. [PubMed: 1095915]
• Commoner, B., A. J. Vithayathil, P. Dolara, S. Nair, P. Madyastha, and G. C. Cuca. 1978. Formation of mutagens in beef and beef extract during cooking. Science 201:913-916. [PubMed: 567374]
• Demerec, M., B. Wallace, and E. M. Witkin. 1948. The gene. Carnegie Inst. Washington Yearb. 47:169-176.
• Demerec, M., G. Bertani, and J. Flint. 1951. A survey of chemicals for mutagenic action on E. coli. Am. Nat. 85:119-136.
• Dolara, P., B. Commoner, A. Vithayathil, G. Cuca, E. Tuley, P. Madyastha, S. Nair, and D. Kriebel. 1979. The effect of temperature on the formation of mutagens in heated beef stock and cooked ground beef. Mutat. Res. 60:231-237. [PubMed: 384210]
• Fukuoka, M., K. Yoshihira, S. Natori, K. Sakamoto, S. Iwahara, S. Hosaka, and I. Hirono. 1980. Characterization of mutagenic principles and carcinogenicity test of dill weed and seeds. J. Pharmacobio-Dyn. 3:236-244. [PubMed: 7411385]
• Gezelius, K., and N. Fries. 1952. Phage resistant mutants induced in Escherichia coli by caffeine. Hereditas 38:112-114.
• Glass, E. A., and A. Novick. 1959. Induction of mutation in chloramphenicol-inhibited bacteria. J. Bacteriol. 77:10-16. [PMC free article: PMC290309] [PubMed: 13620643]
• Guttenplan, J. B. 1978. Mechanisms of inhibition by ascorbate of microbial mutagenesis induced by N-nitroso compounds. Cancer Res. 38:2018-2022. [PubMed: 350382]
• Hardigree, A. A., and J. L. Epler. 1978. Comparative mutagenesis of plant flavonoids in microbial systems. Mutat. Res. 58:231-239. [PubMed: 370575]
• Hayatsu, H., S. Arimoto, K. Togawa, and M. Makita. 1981. a. Inhibitory effect of the ether extract of human feces on activities of mutagens: Inhibition by oleic and linoleic acids. Mutat. Res. 81:287-293. [PubMed: 7029256]
• Hayatsu, H., K. Inoue, H. Ohta, T. Namba, K. Togawa, T. Hayatsu, M. Makita, and Y. Wataya. 1981. b. Inhibition of the mutagenicity of cooked-beef basic fraction by its acidic fraction. Mutat. Res. 91:437-442. [PubMed: 7027035]
• Hirono, I., I. Ueno, S. Hosaka, H. Takanashi, T. Matsushima, T. Sugimura, and S. Natori. 1981. Carcinogenicity examination of quercetin and rutin in ACI rats. Cancer Lett. 13:15-21. [PubMed: 7306940]
• Hollstein, M., and J. McCann. 1979. Short-term tests for carcinogens and mutagens. Mutat. Res. 65:133-226. [PubMed: 159413]
• Hosaka, S., T. Matsushima, I. Hirono, and T. Sugimura. 1981. Carcinogenic activity of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (TRP-P-2), a pyrolysis product of tryptophan. Cancer Lett. 13:23-28. [PubMed: 7306941]
• Howard, J. W., and T. Fazio. 1980. Analytical methodology and reported findings of polycyclic aromatic hydrocarbons in foods. J. Assoc. Off. Anal. Chem. 63:1077-1104. [PubMed: 6997260]
• Inui, N., Y. Nishi, M. M. Hasegawa, and T. Kawachi. 1980. Induction of 8-azaguanine or ouabain resistant somatic mutation of Chinese hamster lung cells by treatment with tryptophan pyrolysis products. Cancer Lett. 9:185-189. [PubMed: 7226150]
• Ishikawa, T., S. Takayama, T. Kitagawa, T. Kawachi, M. Kinebuchi, N. Matsukura, E. Uchida, and T. Sugimura. 1979. In vivo experiments on tryptophan pyrolysis products. Pp. 159-167 in E. C. Miller, editor; , J. A. Miller, editor; , I. Hirono, editor; , T. Sugimura, editor; , and S. Takayama, editor. , eds. Naturally Occurring Carcinogens-Mutagens and Modulators of Carcinogenesis. Japan Scientific Societies Press, Tokyo; University Park Press, Baltimore, Md.
• Johnson, H. G., and M. K. Bach. 1965. Apparent suppression of mutation rates in bacteria by spermine. Nature 208:408-409. [PubMed: 5328386]
• Kasai, H., S. Nishimura, M. Nagao, Y. Takahashi, and T. Sugimura. 1979. Fractionation of a mutagenic principle from broiled fish by high-pressure liquid chromatography. Cancer Lett. 7:343-348. [PubMed: 389417]
• Kasai, H., Z. Yamaizumi, K. Wakabayashi, M. Nagao, T. Sugimura, S. Yokoyama, T. Miyazawa, N. E. Spingarn, J. H. Weisburger, and S. Nishimura. 1980. a. Potent novel mutagens produced by broiling fish under normal conditions. Proc. Jpn. Acad. 56(B):278-283.
• Kasai, H., Z. Yamaizumi, K. Wakabayashi, M. Nagao, T. Sugimura, S. Yokoyama, T. Miyazawa, and S. Nishimura. 1980. b. Structure and chemical synthesis of Me-IQ, a potent mutagen isolated from broiled fish. Chem. Lett. 11:1391-1394.
• Kasai, H., S. Nishimura, K. Wakabayashi, M. Nagao, and T. Sugimura. 1980. c. Chemical synthesis of 2-amino-3-methylimidazo[4, 5-f]quinoline (IQ), a potent mutagen isolated from broiled fish. Proc. Jpn. Acad. 56(B):382-384.
• Kasai, H., Z. Yamaizumi, T. Shiomi, S. Yokoyama, T. Miyazawa, K. Wakabayashi, M. Nagao, T. Sugimura, and S. Nishimura. 1981. Structure of a potent mutagen isolated from fried beef. Chem. Lett. 4:485-488.
• Katoh, Y., M. Tanaka, K. Umezawa, and S. Takayama. 1980. Inhibition of mutagenesis in Chinese hamster V-79 cells by antioxidants. Toxicol. Lett. 7:125-130. [PubMed: 7292522]
• Koehler, P. E., M. E. Mason, and J. A. Newell. 1969. Formation of pyrazine compounds in sugar-amino acid model systems. J. Agric. Food Chem. 17:393-396.
• Krone, C. A., and W. T. Iwaoka. 1981. Mutagen formation during the cooking of fish. Cancer Lett. 14:93-99. [PubMed: 7028249]
• Kubitschek, H. E., and H. E. Bendigkeit. 1958. Delay in the appearance of caffeine-induced T5 resistance in Escherichia coli. Genetics 43:647-661. [PMC free article: PMC1209908] [PubMed: 17247784]
• Kubitschek, H. E., and H. E. Bendigkeit. 1964. Mutation in continuous cultures. I. Dependence of mutational response upon growth-limiting factors. Mutat. Res. 1:113-120. [PubMed: 14237062]
• Lai, C.-N. 1979. Chlorophyll: The active factor in wheat sprout extract inhibiting the metabolic activation of carcinogens in vitro. Nutr. Cancer 1(3):19-21.
• Lai, C.-N., M. A. Butler, and T. S. Matney. 1980. Antimutagenic activities of common vegetables and their chlorophyll content. Mutat. Res. 77:245-250.
• Lee, J. S. K., and L. Y. Y. Fong. 1979. Mutagenicity of Chinese alcoholic spirits. Food Cosmet. Toxicol. 17:575-578. [PubMed: 397915]
• Li jinsky, W., and A. E. Ross. 1967. Production of carcinogenic polynuclear hydrocarbons in the cooking of food. Food Cosmet. Toxicol. 5:343-347. [PubMed: 6054351]
• Li jinsky, W., and P. Shubik. 1964. Benzo(a)pyrene and other polynuclear hydrocarbons in charcoal-broiled meat. Science 145:53-55. [PubMed: 14162692]
• Lintas, C., M. C. De Matthaeis, and F. Merli. 1979. Determination of benzo(a)pyrene in smoked, cooked and toasted food products. Food Cosmet. Toxicol. 17:325-328. [PubMed: 574848]
• Loquet, C., G. Toussaint, and J. Y. LeTalaer. 1981. Studies on mutagenic constituents of apple brandy and various alcoholic beverages collected in Western France, a high incidence area for oesophageal cancer. Mutat. Res. 88:155-164. [PubMed: 7012608]
• MacGregor, J. T., and L. Jurd. 1978. Mutagenicity of plant flavonoids: Structural requirements for mutagenic activity in Salmonella typhimurium. Mutat. Res. 54:297-309. [PubMed: 368618]
• Maga, J. A. 1979. Furans in foods. CRC Crit. Rev. Food Sci. Nutr. 11:355-400. [PubMed: 378551]
• Maruta, A., K. Enaka, and M. Umeda. 1979. Mutagenicity of quercetin and kaempferol on cultured mammalian cells. Gann 70:273-276. [PubMed: 467892]
• Masuda, Y., K. Mori, and M. Kuratsune. 1966. Polycyclic aromatic hydrocarbons in common Japanese foods. I. Broiled fish, roasted barley, shoyu, and caramel. Gann 57:133-142. [PubMed: 4163707]
• Matsukura, N., T. Kawachi, K. Morino, H. Ohgaki, T. Sugimura, and S. Takayama. 1981. a. Carcinogenicity in mice of mutagenic compounds from a tryptophan pyrolyzate. Science 213:346-347. [PubMed: 7244619]
• Matsukura, N., T. Kawachi, K. Wakabayashi, H. Ohgaki, K. Morino, T. Sugimura, H. Nukaya, and T. Kosuge. 1981. b. Liver cancer and precancerous changes in rats induced by the basic fraction of tryptophan pyrolysate. Cancer Lett. 13:181-186. [PubMed: 7296529]
• Matsumoto, T., D. Yoshida, S. Mizusaki, and H. Okamoto. 1977. Mutagenic activity of amino acid pyrolyzates in Salmonella typhimurium TA 98. Mutat. Res. 48:279-286. [PubMed: 327312]
• Matsumoto, T., D. Yoshida, S. Mizusaki, and H. Okamoto. 1978. Mutagenicities of the pyrolyzates of peptides and proteins. Mutat. Res. 56:281-288. [PubMed: 342945]
• Matsumoto, T., D. Yoshida, and H. Tomita. 1981. Determination of mutagens, amino-α-carbolines in grilled foods and cigarette smoke condensate. Cancer Lett. 12:105-110. [PubMed: 7272995]
• McCann, J., and B. N. Ames. 1976. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals: Discussion. Proc. Natl. Acad. Sci. U.S.A. 73:950-954. [PMC free article: PMC336038] [PubMed: 768988]
• McCann, J., E. Choi, E. Yamasaki, and B. N. Ames. 1975. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. U.S.A. 72:5135-5139. [PMC free article: PMC388891] [PubMed: 1061098]
• McKee, R. H., and A. M. Tometsko. 1979. Inhibition of promutagen activation by the antioxidants butylated hydroxyanisole and butylated hydroxytoluene. J. Natl. Cancer Inst. 63:473-477. [PubMed: 287836]
• Meltz, M. L., and J. T. MacGregor. 1981. Activity of the plant flavanol quercetin in the mouse lymphoma L5178Y TK ^+/− mutation, DNA single-strand break, and Balb/c 3T3 chemical transformation assays. Mutat. Res. 88:317-324. [PubMed: 7254225]
• Morino, K., N. Matsukura, T. Kawachi, H. Ohgaki, T. Sugimura, and I. Hirono. 1982. Carcinogenicity test of quercetin and rutin in golden hamsters by oral administration. Carcinogenesis 3:93-97. [PubMed: 7067042]
• Morita, K., M. Hara, and T. Kada. 1978. Studies on natural desmutagens: Screening for vegetable and fruit factors active in inactivation of mutagenic pyrolysis products from amino acids. Agric. Biol. Chem. 42:1235-1238.
• National Cancer Institute. 1978. Bioassay of Aniline Hydrochloride for Carcinogenicity. Carcinogenesis Technical Report Series No. 130. DHEW Publication No. (NIH)78-1385. Carcinogenesis Testing Program, National Cancer Institute, Bethesda, Md. 109 pp. [PubMed: 12799662]
• Nagao, M., M. Honda, Y. Seino, T. Yahagi, and T. Sugimura. 1977. a. Mutagenicities of smoke condensates and the charred surface of fish and meat. Cancer Lett. 2:221-226. [PubMed: 45723]
• Nagao, M., M. Honda, Y. Seino, T. Yahagi, T. Kawachi, and T. Sugimura. 1977. b. Mutagenicities of protein pyrolysates. Cancer Lett. 2:335-340. [PubMed: 324609]
• Nagao, M., T. Yahagi, T. Kawachi, Y. Seino, M. Honda, N. Matsukura, T. Sugimura, K. Wakabayashi, K. Tsuji, and T. Kosuge. 1977. c. Mutagens in foods, and especially pyrolysis products of protein. Pp. 259-264 in D. Scott, editor; , B. A. Bridges, editor; , and F. H. Sobels, editor. , eds. Progress in Genetic Toxicology. Elsevier/North-Holland, New York, Amsterdam, and Oxford.
• Nagao, M., T. Yahagi, T. Sugimura, T. Kosuge, K. Tsuji, K. Wakabayashi, S. Mizusakai, and T. Matsumoto. 1977. d. Comutagenic action of norharman and harman. Proc. Jpn. Acad. 53(2):95-98.
• Nagao, M., T. Yahagi, M. Honda, Y. Seino, T. Matsushima, and T. Sugimura. 1977. e. Demonstration of mutagenicity of aniline and o-toluidine by norharman. Proc. Jpn. Acad. 53(B)):34-37.
• Nagao, M., Y. Takahashi, H. Yamanaka, and T. Sugimura. 1979. Mutagens in coffee and tea. Mutat. Res. 68:101-106. [PubMed: 390384]
• Nagao, M., Y. Takahashi, K. Wakabayashi, and T. Sugimura. 1981. Mutagenicity of alcoholic beverages. Mutat. Res. 88:147-154. [PubMed: 7012607]
• Novick, A. 1956. Mutagens and antimutagens. Brookhaven Symp. Biol. 8:201-215. [PubMed: 13293429]
• Pamuckcu, A. M., Ş. Yalçiner, J. F. Hatcher, and G. T. Bryan. 1980. Quercetin, a rat intestinal and bladder carcinogen present in bracken fern (Pteridium aquilinum). Cancer Res. 40:3468-3472. [PubMed: 7438034]
• Poindexter, E. H., Jr., and R. D. Carpenter. 1962. The isolation of harmane and norharmane from tobacco and cigaret smoke. Phytochemistry 1:215-221.
• Powrie, W. D., C. H. Wu, M. P. Rosin, and H. F. Stich. 1981. Clastogenic and mutagenic activities of Maillard reaction model systems. J. Food Sci. 46:1433-1438, 1445.
• Purchase, I. F. H., E. Longstaff, J. Ashby, J. A. Styles, D. Anderson, P. A. Lefevre, and F. R. Westwood. 1978. An evaluation of 6 short-term tests for detecting organic chemical carcinogens. Br. J. Cancer 37:873-959. [PMC free article: PMC2009661] [PubMed: 354672]
• Rosin, M. P., and H. F. Stich. 1979. Assessment of the use of the Salmonella mutagenesis assay to determine the influence of antioxidants on carcinogen-induced mutagenesis. Int. J. Cancer 23:722-727. [PubMed: 378868]
• Saito, D., A. Shirai, T. Matsushima, and I. Hirono. 1980. Test of carcinogenicity of quercetin, a widely distributed mutagen in food. Teratog., Carcinog., Mutagen. 1:213-221. [PubMed: 6119812]
• Seino, Y., M. Nagao, T. Yahagi, T. Sugimura, T. Yasuda, and S. Nishimura. 1978. Identification of a mutagenic substance in a spice, sumac, as quercetin. Mutat. Res. 58:225-229. [PubMed: 370574]
• Seppilli, A., and G. S. Sforzolini. 1963. [In Italian.] Sulla presenza di idrocarburi policiclici cancerigeni nelle carni cotte alla graticola. Boll. Soc. Ital. Biol. Sper. 39:110-111. [PubMed: 13988000]
• Shamberger, R. J., C. L. Corlett, K. D. Beaman, and B. L. Kasten. 1979. Antioxidants reduce the mutagenic effect of malonaldehyde and β-propiolactone. Part IX, Antioxidants and cancer. Mutat. Res. 66:349-355. [PubMed: 379630]
• Shinohara, K., R.-T. Wu, N. Jahan, M. Tanaka, N. Morinaga, H. Murakami, and H. Omura. 1980. Mutagenicity of the browning mixtures by aminocarbonyl reactions on Salmonella typhimurium TA 100. Agric. Biol. Chem. 44:671-672.
• Simmon, V. F. 1979. In vitro mutagenicity assays of chemical carcinogens and related compounds with Salmonella typhimurium. J. Natl. Cancer Inst. 62:893-899. [PubMed: 372657]
• Spingarn, N. E., and C. T. Garvie. 1979. Formation of mutagens in sugar-ammonia model systems. J. Agric. Food Chem. 27:1319-1321. [PubMed: 544663]
• Spingarn, N., E., L. A. Slocum, and J. H. Weisburger. 1980. a. Formation of mutagens in cooked foods. II. Foods with high starch content. Cancer Lett. 9:7-12. [PubMed: 6989489]
• Spingarn, N. E., H. Kasai, L. L. Vuolo, S. Nishimura, Z. Yamaizumi, T. Sugimura, T. Matsushima, and J. H. Weisburger. 1980. b. Formation of mutagens in cooked foods. III. Isolation of a potent mutagen from beef. Cancer Lett. 9:177-183. [PubMed: 7226149]
• Stich, H. F., W. Stich, M. P. Rosin, and W. D. Powrie. 1980. Mutagenic activity of pyrazine derivatives: A comparative study with Salmonella typhimurium, Saccharomyces cerevisiae, and Chinese hamster ovary cells. Food Cosmet. Toxicol. 18:581-584. [PubMed: 7009348]
• Stich, H. F., M. P. Rosin, C. H. Wu, and W. D. Powrie. 1981. a. Clastogenicity of furans found in food. Cancer Lett. 13:89-95. [PubMed: 7198003]
• Stich, H. F., W. Stich, M. P. Rosin, and W. D Powrie. 1981. b. Clastogenic activity of caramel and caramelized sugars. Mutat. Res. 91:129-136. [PubMed: 7195982]
• Stoltz, D. R., B. Stavric, R. Klassen, and T. Muise. In press a. The health significance of mutagens in foods. In H. F. Stich, editor. , ed. Carcinogens and Mutagens in the Environment. Volume 1, Food Products. CRC Press, Boca Raton, Fla.
• Stoltz, D. R., B. Stavric, D. Krewski, R. Klassen, R. Bendall, and B. Junkins. In press b. Mutagenicity screening of foods. I. Results with beverages. Environ. Mutagen. [PubMed: 7117217]
• Sugimura, T. In press. Food-born genotoxins. In R. Fleck, editor; and A. Hollaender, editor. , eds. Genetic Toxicology: An Agricultural Perspective. Plenum Press, New York.
• Sugimura, T., and M. Nagao. In press. The use of mutagenicity to evaluate carcinogenic hazards in our daily lives. In J. A. Haddle, editor. , ed. Mutagenicity: New Horizons in Genetic Toxicology. Academic Press, New York.
• Sugimura, T., S. Sato, M. Nagao, T. Yahagi, T. Matsushima, Y. Seino, M. Takeuchi, and T. Kawachi. 1976. Overlapping of carcinogens and mutagens. Pp. 191-213 in P. N. Magee, editor; , S. Takayama, editor; , T. Sugimura, editor; , and T. Matsuhima, editor. , eds. Fundamentals in Cancer Prevention. University Park Press, Baltimore, London, and Tokyo.
• Sugimura, T., T. Kawachi, M. Nagao, T. Yahagi, Y. Seino, T. Okamoto, K. Shudo, T. Kosuge, K. Tsuji, K. Wakabayashi, Y. Iitaka, and A. Itai. 1977. Mutagenic principle(s) in tryptophan and phenylalanine pyrolysis products. Proc. Jpn. Acad. 53(1):58-61.
• Sugimura, T., M. Nagao, and K. Wakabayashi. 1982. The metabolic aspects of the comutagenic action of norharman. Pp. 1011-1025 in R. Synder, editor; , D. Parke, editor; , J. J. Kocsis, editor; , D. J. Jollow, editor; , C. G. Gibson, editor; , and C. M. Witmer, editor. , eds. Biological Reactive Intermediates 2. Part B. Plenum Press, New York.
• Takahashi, Y., M. Nagao, T. Fujino, Z. Yamaizumi, and T. Sugimura. 1979. Mutagens in Japanese pickle identified as flavonoids. Mutat. Res. 68:117-123. [PubMed: 390386]
• Takase, S., and H. Murakami. 1966. Fluorescence of sake. I. Fluorescence spectrum of sake and identification of harman. Agric. Biol. Chem. 30:869-876.
• Takayama, S., Y. Katoh, M. Tanaka, M. Nagao, K. Wakabayashi, and T. Sugimura. 1977. In vitro transformation of hamster embryo cells with tryptophan pyrolysis products. Proc. Jpn. Acad. 53(B):126-129.
• Takayama, S., T. Hirakawa, and T. Sugimura. 1978. Malignant transformation in vitro by tryptophan pyrolysis products. Proc. Jpn. Acad. 54(B):418-422.
• Takayama, S., T. Hirakawa, M. Tanaka, T. Kawachi, and T. Sugimura. 1979. In vitro transformation of hamster embryo cells with a glutamic acid pyrolysis product. Toxicol. Lett. 4:281-284.
• Takeda, K., T. Ohta, K. Shudo, T. Okamoto, K. Tsuji, and T. Kosuge. 1977. Synthesis of a mutagenic principle isolated from tryptophan pyrolyzate. Chem. Pharm. Bull. 25:2145-2146. [PubMed: 922993]
• Takeuchi, T., K. Ogawa, H. Iinuma, H. Suda, K. Ukita, T. Nagatsu, M. Kato, and H. Umezawa. 1973. Monoamine oxidase inhibitors isolated from fermented broths. J. Antibiot. 26:162-167. [PubMed: 4798774]
• Tamura, G., C. Gold, A. Ferro-Luzzi, and B. N. Ames. 1980. Fecalase: A model for activation of dietary glycosides to mutagens by intestinal flora. Proc. Natl. Acad. Sci. U.S.A. 77:4961-4965. [PMC free article: PMC349969] [PubMed: 6933540]
• Tohda, H., A. Oikawa, T. Kawachi, and T. Sugimura. 1980. Induction of sister-chromatid exchanges by mutagens from amino acid and protein pyrolysates. Mutat. Res. 77:65-69. [PubMed: 7360158]
• Tsuda, M., Y. Takahashi, M. Nagao, T. Hirayama, and T. Sugimura. 1980. Inactivation of mutagens from pyrolysates of tryptophan and glutamic acid by nitrite in acidic solution. Mutat. Res. 78:331-339. [PubMed: 7003371]
• Tsuda, M., M. Nagao, T. Hirayama, and T. Sugimura. 1981. Nitrite conconverts 2-amino-α-carboline, an indirect mutagen, into 2-hydroxy-α-carboline, a non-mutagen, and 2-hydroxy-3-nitroso-α-carboline, a direct mutagen. Mutat. Res. 83:61-68. [PubMed: 6268972]
• Umezawa, K., A. Shirai, T. Matsushima, and T. Sugimura. 1978. Comutagenic effect of norharman and harman with 2-acetylaminofluorene derivatives. Proc. Natl. Acad. Sci. U.S.A. 75:928-930. [PMC free article: PMC411371] [PubMed: 345280]
• Uyeta, M., T. Kanada, M. Mazaki, S. Taue, and S. Takahashi. 1979. Assaying mutagenicity of food pyrolysis products using the Ames test. Pp. 169-176 in E. C. Miller, editor; , J. A. Miller, editor; , I. Hirono, editor; , T. Sugimura, editor; , and S. Takayama, editor. , eds. Naturally Occurring Carcinogens-Mutagens and Modulators of Carcinogenesis. Japan Scientific Societies Press, Tokyo; University Park Press, Baltimore, Md.
• Uyeta, M., S. Taue, and M. Mazaki. 1981. Mutagenicity of hydrolysates of tea infusions. Mutat. Res. 88:233-240. [PubMed: 7019686]
• Vithayathil, A. J., B. Commoner, S. Nair, and P. Madyastha. 1978. Isolation of mutagens from bacterial nutrients containing beef extract. J. Toxicol. Environ. Health 4:189-202. [PubMed: 633407]
• Wakabayashi, K., K. Tsuji, T. Kosuge, K. Takeda, K. Yamaguchi, K. Shudo, Y. Iitaka, T. Okamoto, T. Yahagi, M. Nagao, and T. Sugimura. 1978. Isolation and structure determination of a mutagenic substance in L-lysine pyrolysate. Proc. Jpn. Acad. 54(B):569-571.
• Wakabayashi, K., M. Nagao, T. Kawachi, and T. Sugimura. 1981. Co-muta-genic effect of norharman with N-nitrosamine derivatives. Mutat. Res. 80:1-7. [PubMed: 7010130]
• Watson, W. A. F. 1982. The mutagenic activity of quercetin and kaempferol in Drosophila melanogaster. Mutat. Res. 103:145-147. [PubMed: 6799807]
• Weisburger, J. H., and N. E. Spingarn. 1979. Mutagens as a function of mode of cooking of meats. Pp. 177-184 in E. C. Miller, editor; , J. A. Miller, editor; , I. Hirono, editor; , T. Sugimura, editor; , and S. Takayama, editor. , eds. Naturally Occurring Carcinogens-Mutagens and Modulators of Carcinogenesis. Japan Scientific Societies Press, Tokyo; University Park Press, Baltimore, Md.
• Yamaguchi, K., H. Zenda, K. Shudo, T. Kosuge, T. Okamoto, and T. Sugimura. 1979. Presence of 2-aminodipyrido[1, 2-a:3',2'-d]imidazole in casein pyrolysate. Gann 70:849-850. [PubMed: 535689]
• Yamaguchi, K., K. Shudo, T. Okamoto, T. Sugimura, and T. Kosuge. 1980. a. Presence of 3-amino-1, 4-dimethyl-5H-pyrido[4, 3-b]indole in broiled beef. Gann 71:745-746. [PubMed: 7227728]
• Yamaguchi, K., K. Shudo, T. Okamoto, T. Sugimura, and T. Kosuge. 1980. b. Presence of 2-aminodipyrido[1, 2-a:3'2'-d]imidazole in broiled cuttlefish. Gann 71:743-744. [PubMed: 7227727]
• Yamaizumi, Z., T. Shiomi, H. Kasai, S. Nishimura, Y. Takahashi, M. Nagao, and T. Sugimura. 1980. Detection of potent mutagens, Trp-P-1 and Trp-P-2, in broiled fish. Cancer Lett. 9:75-83. [PubMed: 6991096]
• Yamamoto, T., K. Sutji, T. Kosuge, T. Okamoto, K. Shudo, K. Takeda, Y. Iitaka, K. Yamaguchi, Y. Seino, T. Yahagi, M. Nagao, and T. Sugimura. 1978. Isolation and structure determination of mutagenic substances in L-glutamic acid pyrolysate. Proc. Jpn. Acad. 54(B):248-250.
• Yasuda, T., Z. Yamaizumi, S. Nishimura, M. Nagao, Y. Takahashi, H. Fujiki, T. Sugimura, and K. Tsuji. 1978. Detection of comutagenic compounds, harman and norharman in pyrolysis product of proteins and food by gas chromatograph-mass spectrometry. Nippon Gan Gakkai Sokai Kiji 37:6).Abstract 41.
• Yoshida, D., and T. Matsumoto. 1978. Changes in mutagenicity of protein pyrolyzates by reaction with nitrite. Mutat. Res. 58:35-40. [PubMed: 362194]
• Yoshida, D., and H. Okamoto. 1980. Formation of mutagens by heating the aqueous solution of amino acids and some nitrogenous compounds with addition of glucose. Agric. Biol. Chem. 44:2521-2522.
• Yoshida, D., T. Matsumoto, R. Yoshimura, and T. Matsuzaki. 1978. Mutagenicity of amino-α-carbolines in pyrolysis products of soybean globulin. Biochem. Biophys. Res. Commun. 83:915-920. [PubMed: 361041]