food-derived mutagens and carcinogens1€¦ · and factors stimulating cancer progression exist....
TRANSCRIPT
[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
Cooked food contains a variety of mutagenic heterocyclic amines. Allthe mutagenic heterocyclic amines tested were carcinogenic in rodentswhen given in the diet at 0.01-0.08%. Most of them induced cancer in
the liver and in other organs. It is noteworthy that the most abundantheterocyclic amine in cooked food, 2-amino-l-methyl-6-phenylimi-dazo(4,5-A|pyridine, produced colon and mammary carcinomasin rats and lymphomas in mice but no hepatomas in either. 2-Amino-3-methylimidazo(4,5-/]quinoline induced liver cancer in monkeys. Forma
tion of adducts with guanine by heterocyclic amines is presumablyinvolved in their carcinogenesis. Quantification of heterocyclic amines incooked foods and in human urine indicated that humans are continuouslyexposed to low levels of them in the diet. These low levels of heterocyclicamines are probably insufficient to produce human cancers by themselves.However, a linear relationship between DNA adduct levels and a widerange of doses of a heterocyclic amine was demonstrated in animals. Itsuggests that even very low doses of heterocyclic amines form DNAadducts and may be implicated in the development of human cancer underconditions in which many other mutagens-carcinogens, tumor promoters,
and factors stimulating cancer progression exist.
Introduction
Diet plays an important role in cancer development: highintakes of total calories and fat enhance cancer development,excessive intake of sodium chloride promotes carcinogenesis inthe stomach, whereas, in contrast, fiber, carotene, and vitaminsprotect against cancer development (1, 2). Foods also containmutagenic and/or carcinogenic substances as very minor components: mycotoxin contaminants, nitrosamines, polycyclic aromatic hydrocarbons, and plant alkaloids (3).
A series of mutagenic-carcinogenic substances have beenfound in cooked meat and fish in the last 15 years. Newheterocyclic amine compounds were isolated by monitoring thefractionation and purification of mutagens by using microbialmutation assays (4-7). These compounds have much highermutagenic activity than other typical mutagens-carcinogens andwere later shown to be carcinogenic in rodents and nonhumanprimates. This review deals mainly with mutagenic and carcinogenic heterocyclic amines that are produced under ordinarycooking conditions.
In 1939, Widmark (8) reported that organic solvent extractsof broiled horse meat induced tumors in mammary glands whenrepeatedly painted on the backs of mice. In the 1970s we becameinterested in whether the smoke produced by broiling meat andfish contained mutagenic and carcinogenic activity, becausecigarette smoke condensate was known to contain many mutagens-carcinogens. We found that a smoke condensate obtainedby broiling fish and trapping the smoke on glass fiber filtersexerted mutagenic activity toward Salmonella typhimuriumTA98 after microsomal metabolic activation (9, 10). TA98 wasmore sensitive than TA 100, indicating that the mutagenic com-
1Presented at "Nutrition and Cancer," the first conference of the InternationalConference Series on Nutrition and Health Promotion. April 17-19. 1991.Atlanta, GA. This study was supported by Grams-in-Aid for Cancer Researchfrom the Ministry of Health and Welfare and the Ministry of Education. Scienceand Culture of Japan, and a Grant-in-Aid from the Ministry of Health andWelfare for a Comprehensive 10-Year Strategy for Cancer Control, Japan.
; To whom requests for reprints should be addressed.
pounds have planar structures that can be inserted between thebase pairs of double-stranded DNA. Charred parts of broiled
fish and meat were also found to be mutagenic to TA98 aftermetabolic activation (9, 10). These findings led to the isolationsof the mutagenic compounds, IQ,' MelQ, MelQx from broiled
fish and meat (5-7). Later PhIP was also isolated as member
of this class of mutagens (11). These heterocyclic amines wereformed by heating mixtures of creatinine, sugars, and aminoacids, which are present in raw meat and fish (12-16). More
recently identified mutagens have been found to contain oxygenatoms (17-19). Before the discoveries of imidazoquinoline and
imidazoquinoxaline compounds, pyrolysates of food components, amino acids, and proteins were shown to contain mutagenic substances. These findings led to the identification ofpyridoindole, dipyridoimidazole, phenylpyridine, and tetraaza-
fluoranthene derivatives as new mutagenic heterocyclic aminesin pyrolysates of amino acids and of amino-a-carboline derivatives as mutagenic compounds in a pyrolysate of protein (4-7).
Some of the heterocyclic amines that were originally isolatedfrom pyrolysates of amino acids and proteins were also recovered from cooked foods (6).
Chemistry of Heterocyclic Amines in Foods
The heterocyclic amines reported so far are listed in Table 1with their chemical names, abbreviations, and sources (11, 17,18, 20-29). They are classified as IQ-type compounds, in which
the amino group is not changed by treatment with 2 HIMsodiumnitrite, and as non-IQ-type compounds, in which the amino
group is converted to a hydroxy group with 2 HIMsodium nitrite(30). The amino group of IQ-type heterocyclic amines is con
verted to a nitro group with 50 mM sodium nitrite and theresulting compound shows a similar mutagenicity to the original compound in the absence of S9 mix (31). Most of theseheterocyclic amines have been synthesized in large quantitiesfor use in long-term experiments in rodents (6, 32). These
compounds remain stable in experimental diets if these dietsare kept cold and dry. They are also sufficiently stable in diluteaqueous solution for biological experiments.
The structures of heterocyclic amines are shown in Fig. 1. Aheterocyclic amine containing oxygen, namely aminomethylim-
idazofuropyridine, can exist as four possible isomers becausethere are two possible positions for both the oxygen and N-
methyl group (17). A mutagenic heterocyclic amine containingoxygen atoms was also isolated from a creatine pyrolysate andidentified as Cre-P-1 (Fig. 1) (18). However, the presence ofCre-P-1 in cooked food has not yet been reported.
3The abbreviations used are: IQ. 2-amino-3-methylimidazo[4,5-/)quinoline;MelQ. 2-amino-3.4-dimethylimidazo[4,5-/]quinoline; MelQx, 2-amino-3,8-di-methylimidazo|4,5-/|quinoxaline; PhIP, 2-amino-1 -methyl-o-phenylimidazo^.S-Ajpyridine; AnC. 2-amino-9//-pyrido[2,3-ft]indole; MeAaC, 2-amino-3-methyl-9//-pyrido[2,3-6]indole; Trp-P-2.3-amino-1 -methyl-5//-pyrido|4,5-e]indole; Glu-P-1. 2-amino-6-methyldipyrido(1,2-a:3',2'-</]imidazole; Cre-P-1,4-amino-1,6-di-methyl-2-methylamino-l//.6//-pyrrolo[3.4-/]benzimidazole-5,7-dione; Trp-P-I,3-amino-1,4-dimethyl-5//-pyrido|4,3-ojindole.
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Table 1 Chemical names, abbreviations, and sources of isolated helerocyclic amines and references
Chemicalname2-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-
1-methyl-o-phenylimidazo^.S-Alpyridine2-Amino-n.n.n-trimethylimidazopyridine2-Amino-n.n-dimelhylimidazopyridine2-Amino-(l
or 3).6-dimelhylfuro[2.3(or3,2)-e|imi-dazo[4.5-ft]p>ridine4-Amino-
1,6-dimethyl-2-methylamino- 1W.6W-pyr-rolo[3.4-/)benzimidazole-5.7-dione3-Amino-
1,4-dimethyl-5//-pyrido[4.3-6]indole3-Amino-1-methyl-5//-pyrido(4,3-o]indole2-Amino-6-methyldipyrido[l,2-a:3'.2'-</]imidazole2-Aminodipyrido|l,2-a:3'.2
-rf]imidazole2-Amino-5-phenylpyridine4-Amino-6-methyl-
1H-2, 5, 10, 106-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-1AaCMeAaCSourceBroiled
sun-driedsardineBroiledsun-driedsardineCreatine-supplememed
friedNorwegianmeatproductFried
beefHeatedmixture ofcreatinine.threonine.
andglucoseHeatedmixture ofcreatinine.glycine,
andglucoseFriedbeefCreatine-supplcmented
friedNorwegianmeatproductCreatine-supplemented
friedNorwegianmeatproductFried
mixture of beef, creatine, andmilkCreatine
pyrolysateTryptophan
pyrolysateTryptophanpyrolysateGlutamic
acidpyrolysateGlutamicacidpyrolysatePhenylalanine
pyrolysateOrnithinepyrolysateSoybean
globulinpyrolysateSoybeanglobulin pyrolysateReference202122232425II222217182626272726282929
Mutagenesis
As described briefly in the introduction, heterocyclic aminesare more mutagenic toward 5. typhimurium TA98 than TA 100.The specific mutagenicities of some heterocyclic amines aremuch stronger than those of typical mutagens-carcinogens suchas aflatoxin B,, 4-nitroquinoline 1-oxide, and benzo[a]pyrene.Moreover, imidazoquinoline and imidazoquinoxaline derivatives, including IQ, MelQ, and MelQx are much more mutagenic than AaC, MeAaC, and PhIP, as shown in Table 2 (4-7). However, these marked differences between mutagenicitiesof heterocyclic amines and other typical mutagens-carcinogenswere not found in cultured mammalian cell systems, such asChinese hamster lung cells with diphtheria toxin resistance (33)and repair-deficient Chinese hamster ovary cells with 6-thiog-uanine resistance (34, 35). Results with these mammalian mutation systems closely reflect carcinogenic potencies, the carcinogenic potencies of IQ, MelQ, and MelQx being almost thesame as those of AaC, MeAaC, and PhIP. One factor responsible for the difference between bacterial systems and mammalian systems would be esterifying enzymes such as acetyltrans-ferase and sulfotransferase. Heterocyclic amines induce chromosomal aberrations (36) and sister chromatid exchanges (34,37-39) in cultured cells in vitro. Heterocyclic amines were alsopositive in a wing spot test with Drosophila melanogaster (40).
Carcinogenesis
Long-term animal experiments with rats and mice fed a dietcontaining heterocyclic amines have been carried out, in mostcases with the maximum tolerable doses (MTD) of the compounds. The results are summarized in Table 3 (41-53). InBALB/c x DBA/2 F, mice tumors developed in the liver,forestomach, lung, blood vessels, hematopoietic system, andlymphoid tissue (42,44,46, 48, 50, 52, 53). In F344 rats tumorsdeveloped in the liver, intestine, skin, oral cavity, mammarygland, Zymbal gland, and clitoral gland (41, 43, 45, 47, 49, 51,53). Most heterocyclic amines were hepatocarcinogens. However, PhIP did not induce hepatomas in rats or mice but insteadinduced colon cancers preferentially in male rats, mammary
gland cancers in female rats (47), and lymphomas in mice ofboth sexes (48).
Injection s.c. of Trp-P-1 resulted in the formation of fibro-sarcomas at the injection site in F344 rats and Syrian goldenhamsters (54). Intragastric intubation of IQ resulted in development of tumors in the mammary gland, liver, and ear ductof SD rats (55). Intestinal tumors developed much more rapidlyin analbuminemic congenie F344 strain rats (F344-Û/A rats)than in F344 rats, when IQ was given with the diet.4 Albumin-
deficient SD rats (NAR rats) were also very sensitive to induction of intestinal tumors by PhIP (56). Hepatocellular carcinomas also developed in cynomolgus monkeys (Macaca fasci-cularis) after repeated administration of IQ by gavage (57).
Metabolism of Heterocyclic Amines and Their Modificationof DNA
Heterocyclic amines are metabolically activated by cyto-chrome P450s with conversion of an amino group to a hydrox-yamino group (58-63). The principal cytochrome P450 isozymeresponsible for this conversion is induced in rat liver by 3-methylcholanthrene. Recent investigations using cloned complementary DNAs for various molecular species of cytochromeP450s driven by vaccinia virus expression vector indicated thatcytochrome P450IA2 is the most effective for metabolic activation of heterocyclic amines (64). Hydroxyamino derivativesof heterocyclic amines are further activated by forming esterswith acetic acid, sulfuric acid, and proline. These esters may bethe ultimate forms producing DNA adducts (58, 61, 65). Theformation of the IQ-guanine adduci is shown schematically inFig. 2 (66). The structures of guanine adducts with Trp-P-2 andGlu-P-1 were also elucidated (67, 68). These DNA adductsshould be responsible for the genetic alteration leading tocarcinogenesis. In vitro experiments using the acetoxyaminoderivative of Glu-P-1 and a plasmid containing the human c-Ha-ras-1 protooncogene sequence demonstrated the hot spotsfor mutation in the region of the CCGG sequence, corresponding to codons il (GCC) and 12 (GGC) (69). The c-Ha-ras
4M. Ochiai el al., manuscript in preparation.
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IQ
NH,N=<1 N-CH,
MelQ
NH,N=<' N-CH,
MelQx 4.8-DiMelQx
IQx
7.8-DiMelQx
PhIP TMIP DMIP
MelFP Cre-P-1
CH,
Trp-P-1
Glu-P-2
Trp-P-2
Phe-P-1
Glu-P-1
Orn-P-1
AoC MeAßC
Fig. I. Structures of mutagenic and carcinogenic heterocyclic amines. SeeTable 1 for abbreviations.
adducts as those in the liver, but these organs show no histológica!precancerous changes, although nephro- and cardiolox-icological effects might appear much later (74, 75). Furthermore, the formation of DNA adducts alone may not be sufficient to produce cancers. This is suggested from a linear relationfound between levels of MelQx-DNA adducts in the liver ofrats and doses ranging from 0.4 ppm to the dose used in acarcinogenicity test, 400 ppm (75). However, the hepalocarcin-ogenic response of mice to various doses (20, 60, 200, and 600ppm) of MelQx seemed to be nonlinear (76). These resultssuggest that the genetic alterations produced by heterocyclicamines are enhanced by liver regeneration induced by heterocyclic amines themselves at higher doses. The linearity of thedose response for carcinogenesis in the intestine and otherorgans has not been examined.
The pharmacokinetics of heterocyclic amines are important.Ingested heterocyclic amines are absorbed from the intestine,and their metabolic activation and inactivation occur mainly inthe liver. Hydroxylation of ring carbons followed by conjugationleads to their inactivation, and detoxified forms of heterocyclicamines are excreted in the urine and feces (77-79). However,the pattern of in vivo metabolism differs for different heterocyclic amines. PhIP is absorbed from the intestine and most ofit is excreted as PhIP in the bile and feces in rats (80). However,in mice treated with polychlorinated biphenyls, little unmeta-bolized PhIP is detected in the feces (81).
Quantification of Heterocyclic Amines and Consideration ofTheir Risk for Cancer Development
Methods have been developed for quantitating heterocyclicamines in various materials such as cooked foods, cigarettesmoke condensate, and urine (6,82-84). The procedures consistof blue-cotton treatment, HCl-methylene dichloride partition,and conventional and high-performance liquid chromatogra-phy. An electrochemical method is effective for detecting imi-dazoquinoline and imidazoquinoxaline derivatives (82). Someexamples of analytical data are given in Table 4 (6, 76). PhIP
mutations were frequently observed in squamous cell carcinomas of the Zymbal gland of rats induced by IQ, MelQ, andMelQx (70). Most of the mutations were found in codon 13and were due to transversions of G to T or G to C.
DNA adduci formation by carcinogenic heterocyclic amineswas detected by the i:P-posllabeling method (71-75). All het
erocyclic amines examined except PhIP produced higher levelsof DNA adducts in the liver than in other organs: with PhIP,which is not a hepatocarcinogen, the adduci level in the liverwas lower than in the olher organs, including the lung, pancreas,and heart (74). Furthermore, the DNA adduci levels of varioushelerocyclic amines in ral liver correlaled well with the carcinogenic potencies of these compounds in the liver. Thus, thelevels of DNA adducls formed by carcinogenic doses of helerocyclic amines in the liver are probably reliable indicators oftheir hepatocarcinogenicities.
Some organs in which the heterocyclic amines form DNAadducts may develop cancers unless animals die from the firstdominant tumor. The presence of DNA adducts and histopalh-ological changes in the pancreas and salivary glands of ratstreated with 0.08% MeAaC, which induces atrophy of theseorgans and is toxic to rats, suggest that lower doses of thiscompound can produce lumors in ihese organs (71). However,DNA from ihe kidney and heart of animals given helerocyclicamines conlains relaiively high levels of Ihe same kinds of DNA
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Table 2 Mutagenicilies of heterocyclic amines and typical carcinogens inSalmonella typhimurium TA98 and TAIOO"
Revertants/iig
CompoundIQMelQIQxMelQx4,8-DiMeIQx7,8-DiMeIQxPhIPCre-P-1Trp-P-1Trp-P-2Glu-P-1Glu-P-2Phe-P-lOrn-P-1A«CMeAaCAflatoxin
B,AF-2*4-Nitroquinoline
1-oxideBenzo(a)pyreneMNNGf/V-Nitrosodieth>
lamineyV-NitrosodimethylamineTA98433.000661,00075,000145,000183,000163.0001,80019.00039.000104,20049.0001,9004156,8003002006.0006.5009703200.000.020.00TAIOO7,00030,0001,50014,0008,0009,9001204001,7001,8003,2001,200232012028.00042,0009.9006608700.150.23
" See Table 1 for abbreviations.* AF-2, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide.c MNNG: Ar-Methyl-A"-nitro-iV-nitrosoguanidine.
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Table 3 Carcinogenicities of heterocyclic amines in rats and mice
ChemicalSpeciesIQ
Rats
MiceMelQ
RatsMiceMelQx
RatsMicePhIP
RatsMiceTrp-P-1
RatsMiceTrp-P-2
MiceGlu-P-1
Rats
MiceGlu-P-2
RatsMiceAaC
MiceMeAaC
MiceConcentration(%)0.03
0.030.03
0.04.0.010.04
0.060.04
0.040.015
0.020.020.05
0.050.05
0.050.080.08Target
organsLiver,
small & large intestines, Zymbalgland, clitoral gland, skin
Liver, loirstoni, irklungLarge
intestine, Zymbal gland, skin,oral cavity, mammary gland
Liver,forestomachLiver,
Zymbal gland, clitoral gland, skinLiver, lung, hematopoieticsystemLarge
intestine, mammary glandLymphoidtissueLiver
LiverLiverLiver,
small & large intestines, Zymbalgland, clitoral gland
Liver, bloodvesselsLiver,
small & large intestines, Zymbalgland, clitoral gland
Liver, bloodvesselsLiver,
bloodvesselsLiver,
blood vesselsReference414243
44454647
48495050515251
525252
Table 4 Amounts of heterocyclic amines in cooked foods"
Amount (ng/g cookedfood)SampleBroiled
beefFried ground beefBroiled chickenBroiled muttonFood-grade beef extractFried cod fishIQ0.19 0.16MelQ
MelQx2.11
0.642.331.013.10
0.03 6.444,8-DiMeIQx0.12
0.810.670.10PhIP15.7
0.5638.142.5
3.6269.2Trp-P-10.21
0.190.12Trp-P-20.25
0.210.180.15AaC1.200.212.50MeAaC0.19
' See Table 1 for abbreviations.
is a relatively abundant heterocyclic amine in cooked food. Thecalculated average intake of carcinogenic heterocyclic amines isabout 0.4—16ng per day, per capita. Carcinogenic heterocyclicamines have been detected in all urine samples examined fromhealthy volunteers eating normal diets but not in the urine ofpostoperative patients receiving parenteral alimentation (85).This indicates that humans are normally continuously exposedto heterocyclic amines in foods and that some level of exposureto heterocyclic amines is unavoidable.
The amounts of individual heterocyclic amines consumeddaily are too small to explain human carcinogenesis, assumingthat the susceptibility of humans to heterocyclic amines is thesame as that of rodents. However, the results of medium-termexperiments in which five heterocyclic amines were administered simultaneously, each at one-fifth and one-twenty-fifth of
NH,<,N-CH, P450IA2
NHOH<N-CH,
NHOR<N-CH,
N-Hydroxy-IQ R:-COCH,-so;
IQ-Guanme base adduct
their carcinogenic dose, suggest that the carcinogenic effects ofheterocyclic amines are additive or synergistic (86). This mayalso be true for other environmental carcinogens. The totalexposure to more than 10 heterocyclic amines formed in cookedfood could be, at most, several 100-fold less than the TD50values of the individual carcinogenic heterocyclic amines (76).Painting a limited amount of Trp-P-2, which itself was notcarcinogenic, on mouse skin resulted in skin tumor formationwhen the skin was treated with a tumor promoter, 12-O-tetra-decanoylphorbol-13-acetate (87). Similarly, a combination of alimited amount of IQ and a sufficient amount of phénobarbitalinduced liver tumors in rats, although the same amount of IQalone did not induce tumors (88). A strain of Long-Evans ratswith cinnamon-like coat color (LEC), which develops hepatitisspontaneously 5 months after birth and hepatomas 14 monthsafter birth, is much more sensitive than normal Long-Evansrats to induction of hepatomas by MelQx.5 Such findings
indicate that the carcinogenic potency of heterocyclic amines isreadily modified by various factors.
Humans are continuously exposed to various mutagens-car-cinogens, both autobiotic and xenobiotic. The multiple geneticalterations present in human cancer cells could be produced bymany kinds of xenobiotic mutagens-carcinogens, each at a very
Fig. 2. Metabolic activation pathway of IQ5H. Sone, M. Maeda, H. Kushida, K. Wakabayashi, K. Enomoto, M. Mori,
T. Sugimura, and M. Nagao, manuscript in preparation.
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low level. In addition, autobiotic formation of oxidative agents 18
in vivo and cell replication increase the chances of geneticalteration.
Total avoidance of exposure to heterocyclic amines is impos- 19sible, but reducing the exposure level as much as possible is 2Qadvisable. For example, charring of food during cooking shouldbe avoided. Direct contact of meat and fish with a naked gasflame or charcoal is also not recommended: a microwave ovenmay be preferable. Cooking meat and fish in aluminum foilwould reduce charring, and a simple method for removingheterocyclic amines is mechanical separation of charred partsof broiled fish and meat from edible portions. Soybean proteinsuppresses mutagen formation in fried hamburger (89). It isdesirable to limit the intake of heterocyclic amines to a mini- 23mum. This principle also holds for any kind of food containingmutagens and carcinogens. The measures to be followed need 24to be realistic and not tedious. Inconvenient measures may notbe accepted by the public.
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1992;52:2092s-2098s. Cancer Res Keiji Wakabayashi, Minako Nagao, Hiroyasu Esumi, et al. Food-derived Mutagens and Carcinogens
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