Items in cart [0]
| [ Top of Page ] [ Home ] [ Contact Us ] [ Help ] [ The National Academies Home ] | ||
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 277
13 Mutagensin Food
As interest in the possible relationship between diet and cancer
has increased in recent years, so have attempts to determine whether
chemical carcinogens may be present in our foods. The foods that we
eat contain a vast number of separate chemical entities: several
thousand as additives and many times this number as natural constitu-
ents. Of course, most of these chemicals are present in relatively
low concentrations, but if potent carcinogens exist, even at low con-
centrations in commonly consumed foods, they may warrant concern. The
problem, therefore, is how to test the very large number of chemicals
present in the complex mixtures we call food to determine whether or
not they may be contributing to our risk for cancer. An adequately
performed chronic feeding study in rodents to determine whether a
chemical is a carcinogen takes several years to complete and analyze
and can cost more than $500,000. Therefore, the use of simpler and
less expensive tests may be considered, at least to help us determine
which chemicals to subject to long-term studies.
As discussed elsewhere in this report, initiation of the carcino-
genic process may involve an alteration in the genetic material of a
cell. Therefore, it is reasonable to suppose that chemicals that
alter DNA (e.g., cause mutations) will have a high probability of
being initiators of carcinogenesis. The fact that DNA is chemically
similar in all living organisms means that even chemicals that cause
mutations in bacteria can be suspected as potential carcinogens in
humans. In several extensive studies conducted in independent lab-
oratories, the correlations between mutagenic activity in bacteria
and carcinogenicity in mammals have been analyzed (McCann and Ames,
1976; McCann et al., 1975; Purchase et al., 1978; Simmon, 1979;
Sugimura et al., 1976~. It is clear from these and other studies
that a chemical found to be mutagenic in any living system should
be suspected of being carcinogenic. However, it is impossible to
provide a single number to express the degree of confidence with
which a mutagen can be considered to be a carcinogen or with which
a nonmutagen can be regarded as a noncarcinogen. This uncertainty
arises from several sources, the most important of which is that the
correlation between mutagenicity and carcinogenicity is highly de-
pendent upon the class of chemical being investigated. For some
classes of chemical carcinogens, such as aromatic amines, polycyclic
hydrocarbons, and direct alkylating agents, there appears to be a
high degree of correlation. However, it is difficult to detect the
mutagenic activity of some types of carcinogens, especially highly
chlorinated compounds. Therefore, judgment must be exercised, in-
cluding a careful consideration of the structure and likely metabo-
lites of the chemical under test, when the significance of a positive
or negative mutagenicity test is being evaluated.
13-1
277
OCR for page 278
278 DIET, NUTRITION,AND CANCER
The utility of mutagenicity tests in identifying chemical carcino-
gens and the subsequent removal of these compounds from products to
which humans are exposed can be illustrated by several historical ex-
amples. These would include the food preservatives 2-~2-furyl)-3-
(5-nitrofuryl~acrylamide (AF-2), which was extensively used in Japan,
the flame retardant chemical tris(2,3-dibromopropyl~phosphate, which
was widely used in children's sleepwear in the United States, and the
hair dye ingredient 2,4-diaminoanisole. The fact that simple muta-
genicity tests correctly predicted the carcinogenic potential of these
chemicals adds to our confidence that correctly interpreted muta-
genicity data can assist us in identifying environmental carcinogens.
The most widely used of the mutagenicity assays is the Salmonella
plate incorporation test, commonly known as the Ames test. In this
assay, a chemical is tested for its ability to induce mutations in
different strains of a bacterium (Salmonella typhimurium). Most
chemical carcinogens and mutagens do not interact directly with DNA.
They require alteration by enzymes in order to become activated. This
process of "metabolic activation" cannot usually be accomplished by
enzymes present in bacteria. Therefore, in the Salmonella test, an
extract of mammalian liver (usually from the rat) is added to provide
the enzymes necessary for metabolic activation.
Many mutagenic test systems other than S. typhimurium have been
used to test chemicals (see review by Hollstein and McCann, 1979~. In
the discussion that follows, however, most of the studies discussed
involve S. typhimurium. Mutagenicity assays have also been used to
investigate the interactions between chemicals. This has resulted in
the discovery of both comutagens, which enhance mutagenic activity of
other chemicals, and inhibitors of mutagenesis. The knowledge that a
chemical is a comutagen or an inhibitor of mutagenesis can provide us
with a useful tool for investigating the metabolic fate and genetic
interactions of chemicals. Modification of mutagenic activity, par-
ticularly as determined in _ vitro test systems, frequently has no
relevance to _ viva effects. Specific in vitro effects of modifiers
of mutagenesis, such as inhibition of a particular metabolizing enzyme,
for example, may not operate or may even have the opposite effect in
living organisms. However, where modification of mutagenesis is ob-
served, the mechanism should be elucidated.
MUTAGENS RESULTING FROM COOKING OF FOODS
Benzo[~]pyrene and Other Polynuclear Aromatic Hydrocarbons
Almost 20 years ago Lijinsky and Shubik (1964) and Seppilli and
Sforzolini (1963) reported that beef grilled over a gas or charcoal
fire contained a variety of polycyclic aromatic hydrocarbons (PAH's).
Benzo~a~pyrene was found in charcoal-broiled steak in levels up to 8
g/kg (Lijinsky and Shubik, 1964~. The source of the PAM's resulting
13-2
OCR for page 279
Mutagens in Food! 279
from charcoal broiling was the smoke generated when pyrolyzed fat
dripped from the meat onto the hot coals. Thus, meats with the highest
fat content acquired the highest levels of these chemicals (Lijinsky
and Ross, 1967~. When meat was cooked in a manner that prevented expo-
sure to the smoke generated by the dripping fat, this source of contam-
ination was either reduced or eliminated (Lijinsky and Ross, 1967;
Lintas _ al., 1979; Masuda et al., 1966~._ _
PAM's have also been found in a variety of smoked foods and in
roasted coffee (Howard and Fazio, 1980~. Vegetables can easily become
contaminated by PAM's from air, soil, or water; fish and shellfish can
assimilate such chemicals from their marine environments (Howard and
Fazio, 1980~. However, unless vegetables or seafood are obtained from
highly contaminated environments, the major source of PAR will probably
be the smoking or cooking of food.
Mutagens from Pyrolyzed Proteins and Amino Acids
During the past few years, it has become clear that PAM'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 acti-
vities of these extracts for histidine-requiring strains of S. typhi-
murium were hundreds or thousands of times greater than could be
accounted for by the reported benzo~aipyrene contents of these cooked
foods. For example, the mutagenic activity of charcoal-broiled beef-
steak was the equivalent to that of approximately 4,500 fig 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 fig of this chemical per kilogram.
The mutagenic activity in the broiled fish and beef could also be
detected in S. typhimurium strain TADS, 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 _ vitro metabolic activation system utilizing the postmitochon-
drial supernatant from homogenized livers of rats pretreated with
polychlorinated biphenyls. Bjeldanes et al. (in press, a, b) have re-
cently completed a series of detailed studies on the cooking condi-
tions 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. typhi-
murium, whereas smoke condensates from pyrolyzed DNA, RNA, starch, or
vegetable oil were only slightly mutagenic (Nagao et al., 1977b).
13-3
OCR for page 280
280 DIET, NUTRITION, AND CANCER
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-Y-
carbolines that are potent mutagens: 3-amino-1,4,-dimethyl-5H-pyrido-
[4,3-b~indole (referred to as Trp-P-l, 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'-diimidazole (Glu-P-l) and 2-aminodipyrido[1,2-a:3',2'-d]-
imidazole (Glu-P-2) (Yamamoto et al., 1978~. The structural simi-
larity between these products of glutamic acid pyrolysate and Trp-P-1
and Trp-P-2 is evident from Figure 13-1.
Wakabayashi et al. (1978) isolated a different, but structurally
related, heterocyclic mutagen from pyrolyzed lysine. This compound
was 3,4-cyclopentenopyrido[3,2-aicarbazole (Lys-P-l). Pyrolysis of
phenylalanine resulted in the formation of the mutagen 2-amino-5-
phenylpyridine (Phe-P-l) (Sugimura et al., 1977~.
When soybean globulin was pyrolyzed, the substances that contrib-
uted 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 (A~C) and 2-amino-3-methyl-9H-pyrido-
[2,3-b~indole (Medic), are quite closely related to the Y-carboline
compounds Trp-P-1 and Trp-P-2 (Yoshida et al., 1978~.
Uyeta _ 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-l, Trp-P-2, and Phe-P-l, 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 A~C and MeA~C (Matsumoto et al.,
1981~. Similarly, A~C could be identified in grilled onions.
13-4
OCR for page 281
Mutagens in Food 2X1
From Amino Acids:
CH3
NH2
HCH3
Trp-P-1
4NH2
CH3
Glu-P-1
Lysine pyrolysate
NJ0N
W H
Lys-P-1
From Proteins:
N>lN~ NH2
H
ARC
Tryptophan pyrolysates
Glutamic acid pyrolysates
Soybean globulin pyrolysates
CH3
~NH2
H
Trp-P 2
O ~r NH2
Glu-P-2
Phenylalanine pyrolysate
JJ tN1NH2
Phe-P-1
~N~N4NH2
H
MeAaC
FIGURE 13-1. Some mutagens from pyrolysates and from cooked foods.
(Figure continued on next page.)
13-5
OCR for page 282
282 DIET, NUTRITION, AND CANCER
Figure 13-1 (continued): Some mutagens from pyrolysates and from
cooked foods.
From Broiled Sardines:
N=(
1
/ N CH3
NH2
IQ
From Broiled Beef:
Protein pyrolysate
NH2
N=<
H3C~,N`~N CH3
MeIQx
Protein pyrolysates
NH2
NJ4` cH3
MeIQ
Two previously unknown mutagens were isolated from broiled sardines
(Kasai et al., 1979~. These were 2-amino-3-methylimidazo[4,5-fiquino-
line (IQ) and 2-amino-3,4-dimethyllmidazo[4,5-fjquinoline (MeIQj, which
are extraordinarily potent mutagens to S. typh~murium strain TA98
(Kasai _ 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
13-1 appear 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.
13-6
OCR for page 283
GO
o
o
o
o
o
4-
o
u'
4-
o
oD
cd
is
a)
To
a:
c
to -
~ A:
v ~
:£
o ~
v
c
o ~
c, ~
so
, x:
~ ~ o
~ ~ Hi
En ~
~ - lo
~ ~ o
c) c
c
so ~
v ~ cr'
:~ ~ ~:
13-7
283
o o o o o ~ ~ ~ ~ ~ —4 ~
0 0 a, ~ a, AD ~ ~ ~ 0 0 ~ 0
0` ~ ~ _' ~ ~ ~ ~ _1 ~ 0`
· e e e e e e e e e e ~ e
01 01 01 01 a1 010101 ala1 01 a1 01
.1 o1 "1 "1 a1 "1"I-1 "1~1 .1 1 Val
~ ~ ~ ~ ~ 0 0 0 0 0 ~ ~
~ ~ ~ ~ g "0 "o "o "0 0 ~ ~ ~
N ~ N ~ ~ ~ ~ ~ ~ ~ N
0 ~ 0 0 0 0 0 0 0
~ ~ : ~ ~ `~, `` ~ ~
-
_
1
C
0
=
64 ~
0 0 0
)" ~
0
~ 0`
e e e
- 1~1~1
01 01 01
"Ivl~l
.1.1 .1
U~
e e e
O 0 00 -
u~ _I 0
`0
l
0 ~
0 0
1 eC:
0
0 ~
V
O C}
O O O
~1 It' O
`0 I_
O O
O O
O
C~ O
0
z
CJ
0
~ i
0
vl
~1
0
0
:~:
0
c
o
~ o
~4 c)
~ ~ ~ ~ ~4
a-r
tJ o ~ c~
Id b b ~d b
C~ C~ C~ C~ C
o
C~
o
o
0`
C
1 _t ~ I
—~ 0 1 1 ~
:^ ~ :~:1 ~ ~ b
eC ~ ~ ~ ^
V +1 1 0 _I
~ 1_ ~ ~ _ -
~ ~i B C ~ N ~
413 O | b ~ J:
1 ^ -
^ · ~ 1 CV' CL ~ 1
O ~ ~ ~4 _t
1 ~ 1 ~ ~— 1
0 ~ 0— o~l 0
~ ~ 0 0 0 1 ~
~ ~ ~ ~ ~ ~^ 3
~ :~1 1 ~L c~ ~ C~
b
1
C
0 a~
_I b _t
_. ~ ~
0 0 0
b b
O O
O O
C~ ~
1 ~
1 C~ _1 ~ C
0 1 0 - 1 _I
:^ O :^ O
b aC _. ~ O
:^ ~ V _ V
" - ~ =1
1 0 ~ 1
:~1a ~ ~ ~ - 1
~ _' 1 C~ 1 1
O — O — O
~ =1 ~ o c
—I 1 ~ ~ _1 -~
_
~: ^ ~C b <~: O
I C~ I :>. I N
e~ — ~ P. ~ 0
o
5 ~
c
s
o
b
O O
O O
O O
~ U~
`0
`0
1 C 1 ~
:^ O ~ O
aC: C aC C
V ~ V _I
_~ _ ~ _
1 ~ 1 1
0
C~ ~ ~ ~
1 — 1 —
O O O O
C N
q'
'=~ a=~
C~ ~ e~
l l l
I ~ ~ ~ ~ ~
0e
~ ~ aC:
E" C
0
0
P.
O
o
z
0
0
00
U)
b
V
0.
0
0
~0
0
z
0
OCR for page 284
284 DIET, NUTRITION, AND CANCER
Four of the mutagenic pyrolysates derived from amino acids or
protein--Trp-P-l, Trp-P-2, Glu-P-l, and AolC--have been shown to in-
duce sister chromatic exchanges in a permanent line of human lympho-
blastoid cells (Tohda et al., 1980~. In addition, the basic fraction
extracted from pyrolyzed tryptophan was found to cause mutations re-
sulting in resistance to ouabain or 8-azaguanine in cultured Chinese
hamster lung cells (Inui et al., 1980~. Trp-P-l, Trp-P-2, and Glu-
P-1 can transform primary Syrian golden hamster embryo cells (Takayama
_ 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 (Taka-
yama et al., 1978~. Although these findings support the potential car-
cinogenicity of these chemicals, a definitive determination of carcino-
genicity must be made in whole animals.
Several of the mutagenic pyrolysates of amino acids or proteins
have been tested for carcinogenicity in viva. Neoplastic nodules,
which are presumed to be precancerous changes, were found in the
livers of Wistar rats given the basic fraction from pyrolyzed trypto-
phan at 0.2% in the diet (Matsukura et al., 1981b). Neither neoplas-
tic 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 _ al., 1979~. Trp-P-1 and Trp-P-2 produced
liver tumors in CDF1 (BALB/c x DBA) mice that were fed a diet con-
taining 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 hemangioendothe-
lial sarcoma of the liver (Hosaka _ al., 1981~. None of the control
animals developed such nodules or tumors. Glu-P-l, Glu-P-2, AaC, and
MeArxC induced hepatomas in mice. Glu-P-1 and Glu-P-2 also induced
hemangioendotheliomas between the scapulae of mice fed diets contain-
ing 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 pre-
dictor of carcinogenicity. However, the presence of a carcinogenic
chemical in a pyrolyzed amino acid or protein mixture does not neces-
sarily imply that the carcinogen will also be present in normally
cooked, uncharred food.
Mutagens Fo~u~ed from Meat at Lower Temperatures
In the experiments concerning the formation of mutagenic pyrolysis
products from amino acids and proteins, temperatures of 250°C or
greater were used (Matsumoto et al., 1977; 1978; Uyeta et al., 1979~.
However, it is now known that simply boiling beef stock at temperatures
13-8
OCR for page 285
Mutagens in Food 285
of approximately 100°C results in the formation of bacterial mutagens
(Commoner _ al., 1978; Vithayathil et al., 1978~. In fact, the forma-_
Lion of mutagens in beef stock has been detected at temperatures as
low as 68°C (Dolara et al., 1979~. Frying of fish at 190°C produces
mutagenic activity (Krone and Iwaoka, 1981~. Mutagenic activity also
results when hamburgers are broiled, even when the surface temperature
does not exceed 130°C (Weisburger and Spingarn, 1979~. A portion of
the mutagenic activity formed from heated beef extract or from fried
beef was found to be due to a chemical with a molecular weight of 198
(Spingarn et al., 1980a), which has now been shown to be IQ (Kasai et
al., 1980a). MeIQx, another heterocyclic mutagenic compound that has
not been identified as an amino acid or protein pyrolysate, has also
been found in fried beef (Kasai et al., 1981~. However, the frying
temperature was not specified. Weisburger and Spingarn (1979)
suggested that this mutagen, formed in beef at moderate temperatures,
may result from a browning reaction between sugars and amines rather
than from the pyrolysis of proteins.
Mutagen Formation Involving Carbohydrates
If the formation of IQ during the cooking of beef results from a
browning reaction, it might be expected that the browning of starchy
foods could also result in the formation of mutagens. Spingarn et al.
(1980b) have observed that the frying of potatoes and the toasting of
bread result in the formation of mutagenic activity, but the chemi-
cal~s) responsible for this activity and their source during the
cooking process remain to be determined.
Browning of foods results from the reaction of amines with sugars.
Using a model system for the browning reaction, Spingarn and Garvie
(1979) found that mutagenic activity occurred when any of six different
sugars, including glucose, were refluxed with ammonium hydroxide. Sev-
eral laboratories have found that heating a mixture of the amino acid
lysine with glucose at temperatures between 100°C and 121°C results
in products that are mutagenic (Powrie et al., 1981; Shinohara et al.,
1980; Yoshida and Okamoto, 1980~. The increase in mutagenic activity
with time paralleled the increase in browning (Shinohara et al., 1980~.
Mutagenic activity could also be produced by using certain amino acids
other than lysine (Powrie et al., 1981; Yoshida and Okamoto, 1980) or
by using fructose rather than glucose (Powrie et al., 1981~.
Chromosome aberrations are alterations in the structures of chromo-
somes that can be observed through a microscope. Such aberrations are
not likely to be heritable. The significance of their induction in
cells _ vitro is not clear, particularly for chemicals unable to in-
duce heritable mutations or _ vivo chromosome aberrations.
Pyrazine and four of its alkyl derivatives--compounds formed by
heating mixtures of sugars and amino acids (Koehler et al., 1969~--
were found to be nonmutagenic to S. typhimurium but capable of induc-
ing chromosome aberrations in cultured Chinese hamster ovary (CHO)
13-9
OCR for page 286
286 DIET, NUTRITION, AND CANCER
cells (Stich et al., 1980~. Commercial caramel and caramelized sam-
ples of several sugars prepared by heating sugar solutions also caused
chromosome aberrations in CHO cells (Stich et al., 1981b). Similarly,
furan and six of its derivatives, which can be produced in foods by
heating carbohydrates (Maya, 1979), were found to cause chromosome
aberrations in CHO cells but to be nonmutagenic to bacteria (Stich et
al., 1981a).
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; Ma cGregor and Jurd, 1978). Quercetin has also been reported to
induce gene conversion in yeast (Hardigree and Epler, 1978), transforma-
tion 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 isorha~nnetin were
found to be responsible for most of the mutagenic activity found in Japa-
nese 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 deter-
mine 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
13-10
OCR for page 287
Mutagens in Food 2SB7
of albino Norwegian rats for 58 weeks resulted in the induction of
tumors in the epithelium of the intestine and urinary bladder. How-
ever, 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 through-
out life, no significant increase in tumor incidence was observed in ACT
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 glyco-
sidase-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. typhi-
murium 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 Wurzner, 1980; Aeschbacher et al., 1980;
Nagao et al., 1979~. Although caffeine has been reported to be muta-
genic 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 carcinogen~city of coffee are discussed in Chap-
ter 12.
Black tea, green tea, and roasted tea were mutagenic to S. typhi-
murium 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 muta-
genic to S. typhimurium strain TA98 (Nagao et al., 1979; Tamura et al.,
1980~. Acid hydrolysis of green or black tea also caused mutagenic
13-11
OCR for page 293
Mutagens in Food 293
REFERENCES
Aeschbacher, H. U., and H. P. Wurzner. 1980. An evaluation of instant
and regular coffee in the Ames mutagenicity test. Toxicol. Lett.
5:139-145.
Aeschbacher, H. U., C. Chappuis, and H. P. Wurzner. 1980. Mutagenicity
testing of coffee: A study of problems encountered with the Ames
Salmonella test system. Food Cosmet. Toxicol. 18:605-613.
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. 1980a. Inhibitory effect of
hemin on the mutagenic activities of carcinogens. Cancer Lett.
11:29-33.
Arimoto, S., Y. Ohara, T. Namba, T. Negishi, and H. Hayatsu. 1980b.
Inhibition of the mutagenicity of amino acid pyrolysis products by
hemin and other biological pyrrole pigments. Biochem. Biophys. Res.
Commun. 92:662-668.
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.
Bjeldanes, L. F., and G. W. Chang. 1977. Mutagenic activity of querce-
tin and related compounds. Science 197:577-578.
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.
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 pro-
tein. Food Chem. Toxicol.
Brown, J. P. 1980. A review of the genetic effects of naturally
occurring flavonoids, anthraquinones and related compounds. Mutat.
Res. 75:243-277.
13-17
OCR for page 294
294 DIET, NUTRITION, AND CANCER
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.
Busk, L., and U. G. Ahlborg. 1980. Retinol (vitamin A) as an inhibitor
of the mutagenicity of aflatoxin B1. Toxicol. Lett. 6:243-249.
Clarke, C. H., and M. J. Wade. 1975. Evidence that caffeine, 8~ethoxy-
psoralen and steroidal diamines are frameshift mutagens for E. cold
K-12. Mutat. Res. 28:123-125.
Commoner, B., A. J. Vithayathil, P. Dolara, S. Nair, P. Madyastha, and
G. C. Cuca. 197 8. Formation of mutagens in beef and beef extract
during cooking. Science 201: 913-916.
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. colt. 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.
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.
Gezelius, K., and N. Fries. 1952. Phage resistant mutants induced in
Escherichia cold by caffeine. Hereditas 38:112-114.
Glass, E. A., and A. Novick. 1959. Induction of mutation in chlor-
amphenicol-inhibited bacteria. J. Bacteriol. 77:10-16.
Guttenplan, J. B. 1978. Mechanisms of inhibition by ascorbate of
microbial mutagenesis induced by N-nitroso compounds. Cancer Res.
38:2018-2022.
Hardigree, A. A., and J. L. Epler. 1978. Comparative mutagenesis of
plant flavonoids in microbial systems. Mutat. Res. 58:231-239.
Hayatsu, H., S. Arimoto, K. Togawa, and M. Makita. 1981a. Inhibitory
effect of the ether extract of human feces on activities of mutagens:
Inhibition by oleic and linoleic acids. Mutat. Res. 81:287-293.
13-18
OCR for page 295
Mutagens in Food 295
Hayatsu, H., K. Inoue, H. Ohta, T. Namba, K. Togawa, T. Hayatsu, M.
lIakita, and Y. Wataya. 1981b. Inhibition of the mutagenicity of
cooked-beef basic fraction by its acidic fraction. Mutat. Res.
91:437-442.
Hirono, I., I. Ueno, S. Hosaka, H. Takanashi, T. Matsushima, T. Sugimura,
and S. Natori. 1981. Carcinogenicity examination of quercetin and
rutin in ACT rats. Cancer Lett. 13:15-21.
Hollstein, M., and J. McCann. 1979. Short-term tests for carcinogens
and mutagens. Mutat. Res. 65:133-226.
Hosaka, S., T. Matsushima, I. Hirono, and T. Sugimura. 1981. Carcino-
genic 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.
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.
Inui, N., Y. Nishi, M. M. Hasegawa, and T. Kawachi. 1980. Induction
of 8-azaguanine or ouabain resistant somatic mutation of Chinese ham-
ster lung cells by treatment with tryptophan pyrolysis products. Cancer
Lett. 9:185-189.
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, J. A.
Miller, I. Hirono, T. Sugimura, and S. Takayama, 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.
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.
Kasai, H., Z. Yamaizumi, K. Wakabayashi, M. Nagao, T. Sugimura, S.
Yokoyama, T. Miyazawa, N. E. Spingarn, J. H. Weisburger, and S.
Nishimura. 1980a. 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. 1980b. Structure and
chemical synthesis of Me-IQ, a potent mutagen isolated from broiled
fish. Chem. Lett. 11:1391-1394.
13-19
OCR for page 296
296 DIET, NUTRITION, AND CANCER
Kasai, H., S. Nishimura, K. Wakabayashi, M. Nagao, and T. Sugimura.
1980c. Chemical synthesis of 2-amino-3-methylimidazo[4,5-fJquino-
line (IQj, 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. Struc-
ture 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.
Koehler, P. E., M. E. Mason, and J. A. Newell. 1969. Formation of pyra-
zine 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.
Kubitschek, H. E., and H. E. Bendigkeit. 1958. Delay in the appearance
of caffeine-induced T5 resistance in Escherichia coli. Genetics
43:647-661.
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.
Lai, C.-N. 1979. Chlorophyll: The active factor in wheat sprout
extract inhibiting the metabolic activation of carcinogens ~n vitro.
Nutr. Cancer 1~3~:19-21.
Lai, C.-N., M. A. Butler, and T. S. Matney. 1980. Antimutagenic activi-
ties of common vegetables and their chlorophyll content. Mutat. Res.
7 7: 245-250.
Lee, J. S. K., and L. Y. Y. Fong. 1979. Mutagenicity of Chinese alco-
holic spirits. Food Cosmet. Toxicol. 17 :575-578.
Lijinsky, W., and A. E. Ross. 1967. Production of carcinogenic polynu-
clear hydrocarbons in the cooking of food. Food Cosmet. Toxicol.
5: 343-347.
Li jinsky, W.t, and P. Shubik. 1964. Benzo~a~pyrene and other poly-
nuclear hydrocarbons in charcoal-broiled meat. Science 145: 53-55.
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.
13-20
OCR for page 297
Mutagens in Food 297
Loquet, C., G. Toussaint, and J. Y. LeTalaer. 1981. Studies on muta-
genic constituents of apple brandy and various alcoholic beverages
collected in Western France, a high incidence area for oesophageal
cancer. Mutat. Res. 88:155-164.
MacGregor, J. T., and L. Jurd. 1978. Mutagenicity of plant flavo-
noids: Structural requirements for mutagenic activity in Salmo-
nella typhimurium. Mutat. Res. 54:297-309.
Maga, J. A. 1979. Furans in foods. CRC Crit. Rev. Food Sci. Nutr.
11:355-400.
Maruta, A., K. Enaka, and M. Umeda. 1979. Mutagenicity of quercetin
and kaempferol on cultured mammalian cells. Gann 70:273-276.
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.
Matsukura, N., T. Kawachi, K. Morino, H. Ohgaki, T. Sugimura, and
S. Takayama. 1981a. Carcinogenicity in mice of mutagenic com-
pounds from a tryptophan pyrolyzate. Science 213:346-347.
Matsukura, N., T. Kawachi, K. Wakabayashi, H. Ohgaki, K. Morino, T.
Sugimura, H. Nukaya, and T. Kosuge. 1981b. Liver cancer and pre-
cancerous changes in rats induced by the basic fraction of tryptophan
pyrolysate. Cancer Lett. 13:181-186.
Matsumoto, T., D. Yoshida, S. Mizusaki, and H. Okamoto. 1977. Muta-
genic activity of amino acid pyrolyzates in Salmonella typhimurium
TA 98. Mutat. Res. 48:279-286.
Matsumoto, T., D. Yoshida, S. Mizusaki, and H. Okamoto. 1978. Muta-
genicities of the pyrolyzates of peptides and proteins. Mutat. Res.
56:281-288.
Matsumoto, T., D. Yoshida, and H. Tomita. 1981. Determination of
mutagens, amino~x-carbolines in grilled foods and cigarette smoke
condensate. Cancer Lett. 12:105-110.
McCann, J., and B. N. Ames. 1976. Detection of carcinogens as muta-
gens in the Salmonella/microsome test: Assay of 300 chemicals:
Discussion. Proc. Natl. Acad. Sci. U.S.A. 73:950-954.
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.
13-21
OCR for page 298
298 DIET, NUTRITION, AND CANCER
McKee, R. H., and A. M. Tometsko. 1979. Inhibition of promutagen acti-
vation by the antioxidants butylated hydroxyanisole and butylated
hydroxytoluene. J. Natl. Cancer Inst. 63: 473-47 7.
Meltz, M. L., and J. T. MacGregor. 1981. Activity of the plant flavanol
quercetin in the mouse lymphoma L5178Y TO /- mutation, DNA single-
strand break, and Balb/c 3T3 chemical transformation assays. Mutat.
Res. 88:317-324.
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.
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.
Nagao, M., M. Honda, Y. Seino, T. Yahagi, and T. Sugimura. 1977a. Muta-
genicities of smoke condensates and the charred surface of fish and
meat. Cancer Lett. 2:221-226.
Nagao, M., M. Honda, Y. Seino, T. Yahagi, T. Kawachi, and T. Sugimura.
1977b. Mutagenicities of protein pyrolysates. Cancer Lett. 2:
335-340.
Nagao, M., T. Yahagi, T. Kawachi, Y. Seino, M. Honda, N. Matsukura,
T. Sugimura, K. Wakabayashi, K. Tsuji, and T. Kosuge. 1977c. Mutagens
in foods, and especially pyrolysis products of protein. Pp. 259-264 in
D. Scott, B. A. Bridges, and F. H. Sobels, 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. 1977d. 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.
1977e. Demonstration of mutagenicity of aniline and o-toluidine by
norha~an. 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.
13-22
OCR for page 299
Mutagens in Food 299
Nagao, M., Y. Takahashi, K. Wakabayashi, and T. Sugimura. 1981.
Mutagenicity of alcoholic beverages. Mutat. Res. 88:147-154.
Novick, A. 1956. Mutagens and antimutagens. Brookhaven Symp. Biol.
8:201-215.
Pamuckcu, A. M., §. Yal~iner, 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.
Poindexter, E. H., Jr., and R. D. Carpenter. 1962. The isolation of
harmane and norharmane from tobacco and cigaret smoke. Phytochem-
istry 1:215-221.
Powrie, W. D., C. H. Wu, M. P. Rosin, and H. F. Stich. 1981. Clasto-
genic 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.
Rosin, M. P., and H. F. Stich. 1979. Assessment of the use of the Sal-
monella mutagenesis assay to determine the influence of antioxidants on
carcinogen-induced mutagenesis. Int. J. Cancer 23:722-727.
Saito, D., A. Shirai, T. Matsushima, and I. Hirono. 1980. Test of car-
cinogenicity of quercetin, a widely distributed mutagen in food.
Teratog., Carcinog., Mutagen. 1:213-221.
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.
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.
Shamberger, R. J., C. L. Corlett, K. D. Beaman, and B. L. Kasten. 1979.
Antioxidants reduce the mutagenic effect of malonaldehyde and S-pro-
piolactone. Part IX, Antioxidants and cancer. Mutat. Res. 66:349-355.
Shinohara, K., R.-T. Wu, N. Jahan, M. Tanaka, N. Morinaga, H. Murakami,
and H. Omura. 1980. Mutagenicity of the browning mixtures by amino-
carbonyl reactions on Salmonella typhimurium TA 100. Agric. Biol. Chem.
44:671-672.
13-23
OCR for page 300
300 DIET, NUTRITION, AND CANCER
Simmon, V. F. 1979. In vitro mutagenicity assays of chemical carcino-
gens and related compounds with Salmonella typhimurium. J. Natl.
Cancer Inst. 62:893-899.
Spingarn, N. E., and C. T. Garvie. 1979. Formation of mutagens in
sugar-ammonia model systems. J. Agric. Food Chem. 27:1319-1321.
Spingarn, N., E., L. A. Slocum, and J. H. Weisburger. 1980a. Formation
of mutagens in cooked foods. II. Foods with high starch content.
Cancer Lett. 9:7-12.
Spingarn, N. E., H. Kasai, L. L. Vuolo, S. Nishimura, Z. Yamaizumi,
T. Sugimura, T. Matsushima, and J. H. Weisburger. 1980b. Formation
of mutagens in cooked foods. III. Isolation of a potent mutagen from
beef. Cancer Lett. 9:177-183.
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.
Stich, H. F., M. P. Rosin, C. H. Wu, and W. D. Powrie. 1981a. Clasto-
genicity of furans found in food. Cancer Lett. 13:89-95.
Stich, H. F., W. Stich, M. P. Rosin, and W. D Powrie. 1981b. Clasto-
genic activity of caramel and caramelized sugars. Mutat. Res.
91:129-136.
Stoltz, D. R., B. Stavric, R. Klassen, and T. Muise. In press a. The
health significance of mutagens in foods. In H. F. Stich, ed. Carcin-
ogens 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.
Sugimura, T. In press. Food-born genotoxins. In R. Fleck and A.
Hollaender, 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, ed. Muta-
genicity: 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, S. Takayama, T. Sugimura, and T.
Matsuhima, eds. Fundamentals in Cancer Prevention. University Park
Press, Baltimore, London, and Tokyo.
13-24
OCR for page 301
Mutagens in Food 301
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 principled) 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, D.
Parke, J. J. Kocsis, D. J. Jollow, C. G. Gibson, and C. M. Witmer, 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.
Takase, S., and H. Murakami. 1966. Fluorescence of sake. I. Fluores-
cence spectrum of sake and identification of barman. 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 trans-
formation in vitro by tryptophan pyrolysis products. Proc. Jpn.
Acad. 54(B):418 - 22.
Takayama, S., T. Hirakawa, M. Tanaka, T. Kawachi, and T. Sugimura. 1979.
_ 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.
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.
Tamura, G., C. Gold, A. Ferro-Luzzi, and B. N. Ames. 1980. Fecalase:
A model for activation of dietary glycosides to mutagens by intes-
tinal flora. Proc. Natl. Acad. Sci. U.S.A. 77:4961-4965.
Tohda, H., A. Oikawa, T. Kawachi, and T. Sugimura. 1980. Induction
of sister-chromatic exchanges by mutagens from amino acid and protein
pyrolysates. Mutat. Res. 77:65-69.
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.
13-25
OCR for page 302
302 DIET, NUTRITION, AND CANCER
Tsuda, M., M. Nagao, T. Hirayama, and T. Sugimura. 1981. Nitrite con-
converts 2-amino-a-carboline, an indirect mutagen, into 2-hydroxy-~-
carboline, a non-mutagen, and 2-hydroxy-3-nitroso-~-carboline, a direct
mutagen. Mutat. Res. 83:61-68.
Umezawa, K., A. Shirai, T. Matsushima, and T. Sugimura. 1978. Comu-
tagenic effect of norharman and barman with 2-acetylaminofluorene
derivatives. Proc. Natl. Acad. Sci. U.S.A. 75:928-930.
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, J. A. Miller, I. Hirono, T.
Sugimura, and S. Takayama, 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.
Vithayathil, A. J., B. Commoner, S. Nair, and P. Madyastha. 1978. Isola-
tion of mutagens from bacterial nutrients containing beef extract. J.
Toxicol. Environ. Health 4:189-202.
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):S69-571.
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.
Watson, W. A. F. 1982. The mutagenic activity of quercetin and kaempferol
in Drosophila melanogaster. Mutat. Res. 103:145-147.
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, J. A. Miller,
I. Hirono, T. Sugimura, and S. Takayama, eds. Naturally Occurring
Carcinogens-Mutagens and Modulators of Carcinogenesis. Japan Scien-
tific 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'-diimidazole in casein
pyrolysate. Gann 70:849-850.
Yamaguchi, K., K. Shudo, T. Okamoto, T. Sugimura, and T. Kosuge. 198Oa.
Presence of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b~indole in broiled
beef. Gann 71:745-746.
13-26
OCR for page 303
Mutagens in Food 303
Yamaguchi, K., K. Shudo, T. Okamoto, T. Sugimura, and T. Kosuge. 1980b.
Presence of 2-aminodipyrido[1,2-a:3'2'-d~imidazole in broiled cuttle-
fish. Gann 71:743-744.
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.
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.
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. Muta-
genicity of amino-a-carbolines in pyrolysis products of soybean
globulin. Biochem. Biophys. Res. Commun. 83:915-920.
13-27
Representative terms from entire chapter:
pyrolysis products