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OCR for page 358
15 Inhibitors of Carcinogenesis
In recent years, a number of foods and constituents of foods have
been studied for their inhibitory effects on carcinogenesis. Results
from both epidemiological and experimental studies have indicated that
some of the substances studied do have inhibitory effects, but the
mechanisms are not yet clear.
This chapter contains a review of the most conclusive data pertain-
ing to the inhibitory effects of nonnutritive constituents of the diet.
EPIDEMIOLOGICAL STUDIES
Epidemiological studies have produced data suggesting that certain
substances in foods may protect against the development of cancer. A
substantial number of these studies have demonstrated an inverse re-
lationship between consumption of vegetables and risk of cancer, es-
pecially cancer of the gastrointestinal tract. Vegetables contain
nutritive constituents with inhibitory capacities (as discussed in
Section A and Chapter 9) as well as nonnutritive inhibitors, which are
described in this chapter. The epidemiological data are not sufficient
to permit a definition of the individual roles played by each of the
several putative inhibitors that may be present in the same food. Never-
theless, the data are of considerable interest even though the mechanism
of inhibition is unclear.
In one study of stomach cancer, Graham et al. (1972) found that con-
sumption of raw vegetables, including Cole slew and red cabbage, was
higher among controls than among cases. In a study of Hawaiian Japanese,
Haenszel _ al. (1972) reported lower risk of stomach cancer for con-
sumers of several Western vegetables, many of which are eaten raw. In a
corresponding study in Japan, the same investigators reported a lower
risk of stomach cancer for consumers of lettuce and celery (Haenszel et
_., 1976~. In case-control studies conducted in Norway and in the
United States (Minnesota), Bjelke (1978) also demonstrated an inverse
relationship between incidence of stomach cancer and the indices for
consumption of vegetables, especially among younger patients and women.
He also reported preliminary findings from a prospective cohort study,
showing a reduced risk of stomach cancer for consumers of large amounts
of vegetables in Norway, but not in the United States. In Japan,
Hirayama (1977) found that the risk for stomach cancer was lower for
nonsmokers who ate green and yellow vegetables than for nonsmokers who
did not eat these vegetables.
358
15-1
OCR for page 359
Inhibitors of Carcinogenesis 359
Much of the epidemiological evidence pertains to cancer of the large
bowel. Modan _ al. (1975) compared cases of colon and rectal cancer
with both hospital and neighborhood controls and found an inverse associ-
ation between colon cancer (but not for rectal cancer) and the frequent
consumption of fiber-containing foods, including cabbage. Other inverse
associations between consumption of fiber-containing foods and colon
cancer (see Chapter 8) could also reflect different intakes of crucif-
erous vegetables. Graham et al. (1978) reported that a decreased risk
for colon cancer was associated with frequent ingestion of raw vegeta-
bles, especially cabbage, Brussels sprouts, and broccoli, in a case-
control study conducted in New York State. Similar but less impressive
findings were obtained for rectal cancer.
Haenszel _ al. (1980) found an inverse association for cabbage con-
sumption in a case-control study of colorectal cancer in Japan, but not
in Hawaii (Haenszel et al., 1973~. In the previously cited, ongoing
cohort study in Minnesota and Norway, Bjelke (1978) noted that the risk
for colorectal cancer is associated inversely with an index of vegetable
consumption in Minnesota, but not in Norway. This result paralleled his
earlier finding that the intake of vegetables, particularly cabbage, by
colorectal cancer cases was less than for controls in Minnesota.
EXPERIMENTAL STUDIES
As discussed in Chapters 8, 9, and 10, certain vitamins, minerals,
and fiber have been found to inhibit some forms of carcinogenesis. Dur-
ing the past decade, studies have shown that foods also contain nonnutri-
tive organic compounds that are also inhibitors of carcinogenesis. These
compounds fall into a category frequently referred to as "secondary plant
constituents." Among these constituents are phenols, indoles, aromatic
isothiocyanates, flavones, protease inhibitors, and the plant sterol
6-sitosterol, which are discussed below along with related studies of the
effects of individual foods.
Effects of Selected Chemicals
l
The administration of selected chemicals in this category has been
shown to inhibit both initiation and promotion of chemically induced
neoplasia in virtually all organs of laboratory animals. As will become
apparent in subsequent discussions, much remains to be learned about
these numerous and virtually omnipresent dietary constituents, including
their possible adverse as well as beneficial effects.
The mechanisms by which these compounds prevent neoplasia is incom-
pletely understood. Some inhibitors, so-called "blocking agents," exert
their effects when administered before and during exposure to carcinogens.
Others act during the promotion phase of carcinogenesis, and still others
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360 DIET, NUTRITION, AND CANCER
inhibit only when given following exposures to inhibitors and promoters
from other external sources. Finally, some inhibitors are effective at
more than one point during the process of carcinogenesis. Of the in-
hibitors identified thus far, the largest number falls into the category
of blocking agents, appearing to act by preventing carcinogens or their
metabolites from reaching or reacting with critical target sites. In
many instances, they alter the activity of enzyme systems that metabolize
carcinogenic agents (Wattenberg, 1981a).
A second general form of inhibition is particularly relevant to pro-
motion. The inhibitor is assumed either to suppress free radical forma-
tion resulting from exposure to tumor promoters or to trap these radi-
cals. Protease inhibitors and phenolic antioxidants have been postulated
to inhibit neoplasia in this manner.
The fact that a compound inhibits chemically induced carcinogenesis
in laboratory animals should not be interpreted as indicating that an
increased intake of the substance is desirable for humans. Knowledge of
possible adverse effects of these compounds is incomplete (see discussion
at the end of this chapter).
Phenols. Two categories of phenolic inhibitors of carcinogenesis
are found in food. One is synthetic and the other occurs naturally. The
synthetic antioxidant, butylated hydroxyanisole (BHA) is a widely used
food additive and has been extensively studied for its capacity to in-
hibit carcinogens induced neoplasia (Wattenberg, 1978~. Table 15-1 lists
experiments in which BHA has been shown to have inhibitory effects. In
these studies, BHA was administered before and/or during exposure to the
carcinogen. BHA has also been shown to inhibit host-mediated mutagenesis
resulting from exposure to hycanthone, metrifonate, praziquantel, and
metronidazole (Batzinger _ al., 1978~. Slaga (1981) reported that BHA
inhibited tumor promotion in the mouse skin when administered after the
carcinogen.
Studies of the mechanism by which BHA inhibits chemically induced
carcinogenesis have shown that this phenolic compound produces a co-
ordinated enzyme response that may be interpreted as causing a greater
rate of detoxification (Wattenberg, 1981a). Mice that have been fed BHA
for 1 to 2 weeks in carcinogen inhibition experiments show marked in-
creases in both glutathione S-transferase activity and tissue glutathione
levels (Benson et al., 1978, 1979~. Glutathione S-transferase is an
important enzyme for detoxifying chemical carcinogens (Benson et al.,
1978; Jakoby, 1978; Wattenberg, 1981a). The activity of uridine diphos-
phate (UDP)-glucuronyl transferase, which is another important conjugat-
ing enzyme in the detoxification systems, is also increased (Cha and
Bueding, 1979~. The feeding of BHA has also been reported to increase
epoxide hydrolase activity (Cha et al., 1978) and to alter the microsomal
monooxygenase system (Lam et al., 1980; Speier et al., 1978~.
15-3
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Inhibitors of Carcinogenesis 361
TABLE 15-1
Inhibition of Carcinogen-Induced Neoplasia by BHAa
Carcinogen Inhibited Species Site of Neoplasm
_
Benzo[a~pyrene Mouse Lung
Benzo~a~pyrene Mouse Forestomach
Benzo[a~pyrene-7-8-dihydrodiol Mouse
7,12-Dimethylbenz~aJanthracene Mouse Lung
Forestomach, lung, and
lymphoid tissue
7,12-Dimethylbenz~aJanthracene Mouse Forestomach
7,12-Dimethylbenz[aJanthracene Mouse Skin
7,12-Dimethylbenz~aJanthracene Rat Breast
7-Hydroxymethyl-12-methyl- Mouse Lung
benz~aJanthracene
Dibenz[_,h~anthracene Mouse Lung-
Nitrosodiethylamine Mouse Lung
4-Nitroquinoline-N-oxide Mouse Lung
Uracil mustard Mouse Lung
Ure than Mouse Lung
Methylazoxymethanol acetate Mouse Large intestine
J
trans-5-Amino-3-[2-(5-nitro-2- Mouse
furyl~vinyl]-1,2,4-oxadiazole
aFrom Wattenberg, 1979a.
15-4
Forestomach, lung,
and lymphoid tissue
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362 DIET, NUTRITION, AND CANCER
The amount of BHA consumed in the average U.S. diet is estimated
to be several milligrams per day at most. This level, when corrected
for body weight, is far less than that given to laboratory animals in
experimental studies. However, exposure to carcinogens is almost cer-
tainly orders of magnitude lower in the human population than in ex-
perimental studies in animals. No conclusion can be drawn at this
time as to whether inhibitory effects of BHA occur at the low concen-
trations of carcinogens to which humans are generally exposed.
Recent studies have shown that several naturally occurring phe-
nolic compounds inhibit carcinogenesis in mice (Wattenberg et al.,
1981a). The phenols studied thus far are cinnamic acid derivatives
that are common constituents of plants. They include o-hydroxycinna-
mic acid, p-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid (caffeic
acid), and 4-hydroxy-3-methoxycinnamic acid (ferulic acid). Limited
data on these derivatives indicate that their inhibition of benzo~a]-
pyrene-induced neoplasia in the mouse is considerably weaker than that
of BHA (Wattenberg et al., 1981a). There are many other phenols in
plants, including plants consumed by humans, but their inhibitory
activity is unknown.
Indoles. Indole-3-acetonitrile, 3,3'-diindolylmethane, and
indole-3-carbinol are found in edible cruciferous vegetables such
as Brussels sprouts, cabbage, cauliflower, and broccoli. Indole-3-
acetonitrile is the most abundant of the three. These indoles have
been studied for their effects on neoplasia induced by benzo~aipyrene
(BaP) and 7,12-dimethylbenz~aJanthracene (DMBA) in rodents (Wattenberg
and Loub, 1978~. When added to the diet of mice before and during ad-
ministration of BaP, all three indoles inhibited BaP-induced neoplasia
of the forestomach and pulmonary adenoma formation. In other experi-
ments, indole-3-carbinol and 3,3'-diindolylmethane inhibited DMBA-
induced mammary tumor formation in female Sprague-Dawley rats. Indole-
3-acetonitrile was inactive in the rat (Wattenberg and Loub, 1978~.
The original rationale for testing the three indoles stemmed from
their ability to alter microsomal monooxygenase oxidase activity. All
three compounds increased the activity of this enzyme system (Loub et
al., 1975; Pantuck et al., 1976) -- indole-3-carbinol and 3,3'-di-
indolylmethane more strongly than indole-3-acetonitrile. The three of
them also increased glutathione S-transferase activity. There have
been no studies in which these compounds were administered after the
carcinogen.
Aromatic Isothiocyanates. Benzyl isothiocyanates and phenethyl
isothiocyanate are also constituents of cruciferous plants. These
aromatic isothiocyanates have been shown to inhibit neoplasia induced
by polycyclic aromatic hydrocarbons (PAH's) when they were adminis-
tered during the initiation phase under several different experimental
conditions. These results were obtained when the aromatic isothio-
cyanate was fed both before and during administration of the PAM's
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Inhibitors of Carcinogenesis 363
(Wattenberg, 1977, 1979b). Little is known about their mechanism of
inhibition other than the fact that benzyl isothiocyanate in a potent
inducer of glutathione S-transferase activity. In further studies,
mammary tumor formation resulting from exposure to DMBA was inhibited
by the administration of benzyl isothiocyanate subsequent to the car-
cinogen. It has also been demonstrated that this compound inhibited
1,2-dimethylhydrazine-induced neoplasia of the large intestine when
the exposures were begun 1 week after administration of the carcinogen
(Wattenberg, 1981b). The mechanism of these inhibitory effects is not
known.
Flavones. The study of flavones (found in fruits and vegetables)
as possible inhibitors was undertaken as a result of data showing that
several inducers of increased microsomal mixed function oxidase acti-
vity inhibit chemically induced carcinogenesis.
Inhibition of BaP-induced carcinogenesis has been studied with
three flavones: two synthetic compounds -- 6-naphthoflavone (5,6-
benzoflavone) and quercetin pentamethyl ether -- and one naturally
occurring compound -- rutin (3,3',4',5,7-pentahydroxyflavone-3-
rutinoside). Quercetin pentamethyl ether is sometimes substituted
for tangeretin, a naturally occurring pentamethoxy flavone found in
citrus fruits. All three flavones induce aryl hydrocarbon hydroxylase
(AHH) activity: 6-naphthoflavone is the most potent inducer, quercetin
pentamethyl ether is a moderate inducer, and rutin has the weakest
inducing capacity. When added to the diet of A/HeJ mice subsequently
challenged with orally administered BaP, 6-naphthoflavone caused
almost total inhibition of pulmonary adenoma formation, and quercetin
pentamethyl ether reduced the number of these neoplasms by one-half.
The number of adenomas was the same in animals fed rutin and the con-
trol diet. Thus, the inhibitory effects of BaP-induced neoplasia
paralleled the potency of the three flavones in inducing increased AHH
activity (Wattenberg and Leong, 1968, 1970~. Recently, 6-naphthofla-
vone has been shown to induce activity of conjugating enzymes, includ-
ing glutathione S-transferase.
The mutagenic flavones have multiple hydroxyl groups. Flavones
exerting protective effects do not have free polar groups; they either
contain methoxy substituents or are unsubstituted (MacGregor and Jurd,
1978~. The mutagenic and carcinogenic effects of flavones are dis-
cussed in Chapter 13.
Protease Inhibitors. Protease inhibitors are widely distributed
in plants, and are particularly abundant in seeds. Soybeans, a major
source of protein in many vegetarian diets, and lima beans contain a
variety of these compounds.
Protease inhibitors have in common the ability to inhibit pro-
tease enzymes as well as tumor promotion (Troll, 1981~. Inhibition of
this type has been demonstrated using the two-stage model to study
15-6
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364 DIET, NUTRITION, AND CANCER
skin carcinogenesis in the mouse. In addition, a reduced incidence
of breast cancer has been observed in irradiated rats fed a diet rich
in protease inhibitors after exposure to the radiation (Troll, 1981~.
Protease inhibitors have also been shown to block promotion in in
vitro systems. The transformation of C3HlOTl/2 cells by x-rays fol-
lowed by incubation with 12-o-tetradecanoylphorbol-13-acetate (TPA) is
blocked if protease inhibitors are present after exposure to the radi-
ation (Kennedy and Little, 1981~. Troll (1980) suggested that pro-
tease inhibitors prevent formation of free radicals by tumor promoters.
Since BRA and some related antioxidants inhibit promotion, there may
be common mechanisms among inhibitors that would lead to synergistic
effects.
6-Sitosterol. 6-Sitosterol is a common plant sterol that is pres-
ent in many different vegetables and vegetable oils. Its protective
effects have been studied in an experimental system with N-nitroso-
methylurea--a direct-acting carcinogen. 6-Sitosterol reduced the in-
cidence of large bowel cancer from 54% to 33% when fed in the diet
through the entire course of the experiment or only during the promo-
tion phase of carcinogenesis (Cohen and Raicht, 1981; Raicht et al.,
1980~. Other plant sterols of similar structure have not been studied
for potential inhibitory effects.
Effects of Individual Foods on Carcinogen-Metabolizing Enzyme Systems
Studies in Animals. Several enzyme systems involved in metaboliz-
ing carcinogens are highly responsive to compounds entering the body
from the environment. For example, animals fed purified diets and
kept in filtered air show almost no monooxygenase oxidase activity for
PAM's and azo dyes in the small bowel and lungs (Wattenberg, 1970,
1972).
One source of naturally occurring inducers of increased microsomal
monooxygenase activity is vegetables. In laboratory animals, crucif-
erous vegetables such as Brussels sprouts, cabbage, cauliflower, and
broccoli have a moderately potent inducing effect on monooxygenase
oxidase activity. Other vegetables such as alfalfa, spinach, and
celery have some inducing activity, but it is weak (Wattenberg, 1972~.
More recently, studies have been conducted to examine the effects
of individual foods on glutathione S-transferase, which is a major
detoxification system that catalyzes the binding of a vast variety of
electrophiles to the sulfhydryl group of glutathione (Chasseaud, 1979;
Jakoby, 1978~. Since the reactive ultimate carcinogenic forms of chem-
icals are electrophiles, the glutathione S-transferase system takes on
considerable importance as a mechanism for carcinogen detoxification.
Enhancement of the activity of this system, as measured in vitro, has
been shown to be associated with decreased response of tissues to
chemical carcinogens (Sparnins and Wattenberg, 1981~.
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Inhibitors of Carcinogenesis 365
The activity of glutathione S-transferase is much greater in tis-
sues of animals fed normal rather than purified diets. Diets contain-
ing large quantities of cruciferous vegetables induce increased gluta-
thione S-transferase activity (Sparnins, 1980~. The extent to which
green coffee beans induce such activity is quite remarkable. In mice
fed a diet containing green coffee beans, glutathione S-transferase
activity was enhanced sixfold in the liver and sevenfold in the small
bowel (Sparnins et al., 1981~. Considerably less inducing activity
has been found in roasted coffee beans, commercial instant coffee, and
instant decaffeinated coffee, indicating that some destruction of the
inducing compounds has occurred during processing. Two potent inducers
of glutathione S-transferase activity have been isolated from green
coffee beans. These compounds are kahweol palmitate and cafestol
palmitate (Lam et al., 1982~.
Studies in Humans. Diets containing large amounts of cabbage and
Brussels sprouts were fed to healthy volunteers between 21 and 32 years
of age. The effects of this diet on the metabolism of antipyrine and
phenacetin were studied. These compounds, like many carcinogens, are
initially metabolized by the microsomal monooxygenase system and their
oxidative metabolites subsequently conjugated. The results indicated
that subjects eating diets rich in vegetables metabolized both drugs
more rapidly than did subjects on a control diet (Pantuck et al.,
1979).
Possible Adverse Effects of Inhibitors
Several of the inhibitors discussed above, e.g., indole-3-carbinol
and 3,3'-diindolylmethane, are moderate or strong inducers of micro-
somal monooxygenase activity. Compounds with this characteristic are
potentially hazardous (Wattenberg, 1979a). For example, the micro-
somal monooxygenase enzyme system produces two different categories of
carcinogen metabolites: detoxification products and activated species.
In the metabolism of aromatic amines, ring hydroxylation results in de-
toxification, whereas hydroxylation of the nitrogen leads to the forma-
tion of a proximate carcinogen. Thus, administration of compounds that
increase monooxygenase activity can result in competing reactions, and
the net effect is uncertain.
A second possible adverse effect of compounds that induce micro-
somal monooxygenase activity is that they may act as tumor promoters.
An additional consideration is that the microsomal monooxygenase sys-
tem metabolizes some physiological compounds such as steroid hormones.
This alteration of activity might cause adverse effects by changing
the levels of these compounds or their metabolites.
Two compounds have been shown experimentally to have dual effects,
i.e., they can inhibit carcinogenesis and they also can cause or en-
hance neoplasia. One such compound is butylated hydroxytoluene (BHT).
This compound can inhibit carcinogenesis under certain conditions. It
is also a tumor promoter, as discussed in Chapter 14. The second com-
pound is coumarin, which can inhibit carcinogenesis, but when fed to
15-8
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366 DIET, NUTRITION, AND CANCER
rats for 18 months, it produces bile duct carcinomas. Thus, a particu-
lar compound may have diverse effects. When this occurs, its overall
impact is difficult to predict.
S UMMARY
Epidemiological Studies
Epidemiological evidence from several case-control studies
suggests that certain vegetables, especially cruciferous vegetables,
have a possible protective effect against cancer at several sites.
The responsible constituent or constituents cannot be identified on
the basis of present information.
Experimental Studies
Food contains many compounds that have been shown to inhibit
carcinogenesis in laboratory animals. Because there are so many of
these compounds and because their nature is so diverse, they are
likely to be present in the diet of most humans.
The mechanisms of inhibition are incompletely understood. Some
inhibitors modify the activity of enzyme systems that have the capa-
city to detoxify carcinogenic agents. Others may act by suppressing
formation of free radicals or by trapping free radicals arising during
the process of carcinogenesis.
A number of compounds inhibiting chemically induced carcinogenesis
in laboratory animals are present in cruciferous vegetables. These
compounds include aromatic isothiocyanates, indoles, and phenols.
CONCLUSION
The committee concluded that there is sufficient epidemiological
evidence to suggest that consumption of certain vegetables, especially
carotene-rich (i.e., dark green and deep yellow) vegetables and cru-
ciferous vegetables (e.g., cabbage, broccoli, cauliflower, and Brussels
sprouts), is associated with a reduction in the incidence of cancer at
several sites in humans. A number of nonnutritive and nutritive com-
pounds that are present in these vegetables also inhibit carcinogenesis
in laboratory animals. Investigators have not yet established which,
if any, of these compounds may be responsible for the protective effect
observed in epidemiological studies.
The fact that a compound has been shown to inhibit carcinogen-
induced neoplasia in laboratory animals should not be interpreted as
indicating that it is desirable for humans. These compounds may have
adverse effects. Information on this subject is incomplete.
15-9
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Inhibitors of Carcinogenesis 367
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Inhibitors of Carcinogenesis 369
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Section C Patters of Diet and Cancer
In Sections A and B the committee reviewed the evidence concerning
the role of specific nutrients and nonnutritive dietary components.
This section provides a more comprehensive assessment of the overall
contribution of diet to cancer.
Chapter 16 contains an overview of the evidence relating diet to
cancer in light of the trends in cancer incidence and mortality and the
influence of other environmental factors on these trends. In Chapter
17, the epidemiological evidence is reassembled by each cancer site to
provide a perspective on the contribution of all dietary factors to the
occurrence of cancer at specific sites.
The committee recognized at the start that the current state of
knowledge is insufficient to permit a precise quantification of the
effect of the diet on the incidence of cancer. Therefore, in Chapter
18, the committee has presented merely a framework for assessing risk,
with particular emphasis on the different elements that need to be con-
sidered when assessing the risks posed by initiators and modifiers that
may be present in the diet. Attempts made by other investigators to
determine the quantitative contribution of diet to the overall risk of
cancer are also discussed.
371
C-1
Representative terms from entire chapter:
inhibitory effects
