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5 Lipids (Fats and Cholesteroll
EPIDEMIOLOGICAL EVIDENCE
_ .
Fats
Of all the dietary factors that have been associated epidemiologi-
cally with cancers of various sites, fat has probably been studied most
thoroughly and produced the greatest frequency of direct associations.
However, since dietary fat is highly correlated with the consumption of
other nutrients that are present in the same foods, especially protein in
Western diets, it is not always possible to attribute these associations
to fat intake per se with absolute certainty.
~ _
Breast Cancer. Several international correlation studies have shown
direct associations between per capita fat intake and breast cancer in-
cidence or mortality (Armstrong and Doll, 1975; Carroll, 1975; Drasar and
Irving, 1973; Gray et al., 1979; Hems, 1978; Knox, 1977~. In general,
the correlations were higher for total fat than for the other dietary
factors considered (e.g., animal protein, meat, specific fat components,
and oils). Some of the similarities in the findings undoubtedly reflect
the overlapping data sets used in these studies rather than reproduced
results.
In other correlation studies, intracountry data sets have been used
to compare dietary fat intake and breast cancer. Gaskill et al. (1979)
compared per capita intake of various foods by state within the United
States with corresponding breast cancer mortality rates and found a
significant direct correlation with fat intake when results from all
states studied were combined. The correlation disappeared, however,
when the southern states were excluded from the analysis or when they
controlled for age at first marriage (as a reflection of age at first
pregnancy) or median income. Their results suggested that dairy products
as a class increased the risk of breast cancer. Hems (1980) noted that
time trends for breast cancer mortality in England and Wales from 1911
to 1975 correlated best with corresponding per capita intake patterns
for fat, sugar, and animal protein one decade earlier. In studies based
on personal interview data, Kolonel et al. (1981) correlated individual
consumption of fat with ethnic patterns of breast cancer incidence in
Hawaii. These investigators found significant associations with total
fat, with animal fat, and with both saturated and unsaturated fats.
The findings of three case-control studies support a role for dietary
fat in the risk for breast cancer. Phillips (1975) reported a direct
association between frequency of consumption of high-fat foods and breast
cancer in a study of 77 breast cancer cases and matched controls among
73
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74 DIET, NUTRITION, AND CANCER
Seventh-Day Adventists in California. Miller et al. (1978) also found
a weak direct association, but no evidence of a dose response, between
total fat consumption (based on quantitative dietary histories) and
breast cancer in a study of 400 cases and 400 matched neighborhood
controls in Canada.
In the third case-control study, Lubin et al. (1981) found signifi-
cant increasing trends in relative risk with more frequent consumption of
beef and other red meat, pork, and sweet desserts. Analysis of computed
mean daily nutrient intake supported a link between breast cancer and
consumption of animal fat and protein.
Nomura _ al. (1978) compared the diets consumed by husbands of women
with and without breast cancer. (The men were participants in a pro-
spective cohort study of Japanese men in Hawaii.) These investigators
reported a direct association between consumption of high fat diets by
the husbands and breast cancer in their wives, who were assumed to have
adhered to similar eating patterns.
Prostate Cancer. Prostate cancer has also been associated epide-
-
miologically with fat intake. International data on mortality, but not
incidence, indicate that there is a strong direct correlation of per
capita total fat intake and cancer at this site (Armstrong and Doll,
1975~. Howell (1974) reported similar results from a study based on a
rank correlation with mortality in 41 countries. In Hawaii, the inci-
dence of prostate cancer in four ethnic groups was highly correlated
with consumption of both animal and saturated fat (Kolonel et al.,
1981~. In the mainland United States, Blair and Fraumeni (1978) corre-
lated prostate cancer mortality by county with dietary variables. They
observed that counties with a high risk for prostate cancer among whites
had correspondingly high per capita fat intakes among the same population.
Hirayama (1977) observed that one of the most notable dietary changes in
Japan since 1950 is increased per capita fat intake and that this change
parallels a striking increase in mortality from prostate cancer.
Prostate cancer has been associated with dietary fat in two case-
control studies. In an ongoing study based on 111 cases with prostate
cancer and 111 matched hospital controls, Rotkin (1977) has found that
the cases had consumed high fat foods with greater frequency than had
the controls. Schuman et al. (1982) also reported a more frequent con-
sumption of foods with high animal fat content by cases than by controls.
Cancer of Other Reproductive Organs. Other reproductive organs for
which there have been associations between dietary fat and cancer include
the testes, corpus uteri, and ovary. Armstrong and Doll (1975) found
direct correlations between per capita intake of total fat and incidence
of cancer of the testes and corpus uteri and mortality from ovarian can-
cer. Lingeman (1974) also correlated mortality from ovarian cancer with
international data on fat intake. Kolonel et al. (1981) found a direct
association between ethnic patterns of total, animal, saturated, and
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Lipids (Fats and Cholesterop 75
unsaturated fat consumption in Hawaii and incidence of cancer of the
corpus uteri.
Gastrointestinal Tract Cancer. Dietary fat has also been associated
-
with cancer at several sites in the gastrointestinal tract. In only one
case-control study, however, has an association of stomach cancer with
dietary fat been suggested. In that study, Higginson (1966) reported
more frequent consumption of fried foods and greater use of animal fats
in cooking by gastric cancer cases than by controls. Graham et al.
(1972) failed to confirm this finding in a subsequent study of 168 gas-
tric cancer cases matched to hospital controls.
Although time-trend data in Japan (Hirayama, 1977) and one inter-
national correlation study (Lea, 1967) have shown associations of fat
intake with pancreatic cancer, most epidemiological data pertain to
cancers of the large bowel. Armstrong and Doll (1975) reported direct
correlations between colon and rectal cancer incidence and mortality and
per capita intake of total fat, based on international data. Knox (1977)
also reported a strong correlation between mortality from cancer of the
large intestine (excluding rectum) and per capita total fat intake, and
only a slightly weaker correlation between mortality from rectal cancer
and intake of total fat and animal fat.
After reviewing their data from an earlier study, Enig et al. (1979)
retracted their original suggestion that colon cancer was directly cor-
related with intake of total, saturated, and vegetable fat, but not with
animal fat. gingham et al. (1979) calculated average intakes of nutrients
by populations in different regions of Great Britain. They found no sig-
nificant association of fat intake with mortality from colon and rectal
cancers. Lyon and Sorenson (1978) also reported little difference in fat
intake between the population of Utah (with a low risk for colon cancer)
and that of the United States as a whole.
The contrast between the strong international correlations and the
lack of associations within countries is striking. One possible expla-
nation is that the regional food intake data within a country are based
on means of individual consumption data and, thus, may be too uniform to
demonstrate any strong association with risk of colon or rectal cancer.
In contrast, the variation in fat intake among countries is much greater,
thereby facilitating the demonstration of associations.
MacLennan et al. (1978) compared the diets of adult men in two Scandi-
navian populations with different risks for colon cancer (high risk for
Danes in Copenhagen and low risk for Finns in Kuopio). These studies,
which were based on food diaries, indicated that the consumption of fat
was similar for both groups, but that there were differences in fiber
intake (see Chapter 8~. Reddy et al. (1978) also studied this low risk
Finnish population and compared their diets to those of a high risk
population in New York. They too found no difference between groups in
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76 DIET, NUTRITION, AND CANCER
total fat intake, but noted that a higher proportion of total fat was
consumed as dairy products by the Finns and as meat by the New Yorkers.
This observation raises the possibility that the source as well as the
quantity of dietary fat may be relevant.
In a case-control study conducted in parallel with the study on
breast cancer (described above), Phillips (1975) found a direct asso-
ciation between colon cancer and the frequent consumption of high-fat
foods by Seventh-Day Adventists. In a study of cases and hospital con-
trols among blacks in California, Dales et al. (1978) observed a direct
association between risk of colon cancer and frequent consumption of
foods high in saturated fat. The association was strongest for those
who consumed diets high in saturated fat and low in fiber content. Total
fat consumption, estimated from frequency data, was also reported to be
higher among large bowel cancer cases than among controls in a study
conducted in Puerto Rico (Martinez et al., 1979~.
Dietary histories were used to estimate nutrient intake in a case-
control study conducted by Jain et al. (1980) in Canada. They reported
a direct association (including a dose response) between risk of both
colon and rectal cancer and consumption of fat, especially saturated
fat. The elevated risks persisted after adjustment for other nutrients
in the diet.
Several reports on meat consumption are relevant to this discussion
since meat can be an important source of dietary fat, especially satu-
rated fat. Berg and Howell (1974) and Howell (1975) reported a high
correlation between colon cancer mortality and meat intake (particularly
beef), based on international per capita intake data. In Hawaii,investi-
gators reported a direct association between frequency of meat, especially
beef, consumption and large bowel cancer among Japanese cases and hospital
controls (Haenszel et al., 1973~. This finding was not reproduced in
studies conducted in Buffalo, New York (Graham et al., 1978) and in Japan
(Haenszel et al., 1980), nor in parallel cohorts followed prospectively
in Minnesota and Norway (Bjelke, 1978~. Furthermore, Enstrom (1975) has
noted that trends in beef intake in the United States do not correlate
with trends in the incidence of and mortality from colorectal cancer.
Meat consumption has also been associated with pancreatic cancer.
In a case-control study conducted in Japan, Ishii et al. (1968) found a
direct association between meat consumption by men and mortality from
pancreatic cancer. Their findings were based on responses to mailed
questionnaires, most of which were completed by relatives of deceased
cases. Hirayama (1977) reported a relative risk of 2.5 for daily meat
intake and incidence of pancreatic cancer in a prospective cohort study
of 265,118 Japanese.
Summary. The results from a substantial number of epidemiological
studies have indicated an association between dietary fat and cancers of
the gastrointestinal tract (especially the large bowel) and of endocrine
target organs (especially the breast and prostate). Some studies of
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Lipids (Fats and Cholesterol) 77
large bowel cancer were conducted on groups of relatively homogeneous
populations, and some were not specifically designed to test the hypothe-
sis that fat consumption is associated with colon cancer. The studies
designed specifically to test this hypothesis (e.g., Dales et al., 1978;
Jain et al., 1980) tended to show the most striking direct associations,
especial ~ when the possible confounding effects of dietary fiber were
considered. The evidence for cancer of the breast and prostate is more
consistent than that for large bowel cancer. The results of the most
thorough case-control study of breast cancer yet reported (Miller et al.,
1978) were only weakly positive, however, partly reflecting the fact that
recent food consumption was measured rather than dietary intake patterns
earlier in life, which may have been the more relevant exposure period.
(Studies of changing breast cancer incidence among Japanese migrants to
the United States and their descendants, for example, suggest that
early-life exposures are important determinants of breast cancer risk.)
Cholesterol
High-fat diets have been associated with atherosclerosis--a condition
that has also been associated with elevated serum cholesterol levels.
Therefore, there has been interest in studying the relationship of serum
cholesterol levels as well as cholesterol intake to the incidence of can-
cer. Most of the studies described below were designed to examine the
association between cholesterol and cardiovascular disease, and were not
specifically intended to measure cancer incidence or mortality. However,
the opportunity provided by these long-term studies of cardiovascular
disease in which serum cholesterol levels of the subjects were determined
at the beginning of the study has resulted in a number of different re-
ports on observed associations.
Using per capita food intake data from 20 industrialized nations and
simple correlation analysis, Liu et al. (1979) showed that there was a
strong direct correlation between per capita intake of total fat and
cholesterol and the mortality rate for colon cancer, but that there was
an inverse correlation for fiber intake. Cross-classification showed a
highly significant association for cholesterol, but not for fat or fiber.
These investigators suggested that the data support a causal relationship
between dietary cholesterol and colon cancer.
Pearce and Dayton (1971) conducted an 8-year clinical trial in which
groups of 422 and 424 men were fed a conventional diet or one containing
high levels of polyunsaturated fat (to lower cholesterol levels), respec-
tively. Incidence of cancer deaths in the groups on the experimental
diet was higher. In a similar experiment conducted in Finland, Miettinen
_ al. (1972) also found more carcinomas in the test group. A study
group, convened to examine cancer incidence in men from five controlled
trials of cholesterol-lowering diets, found little difference in relative
risks (Ederer et al.. 1971).
_ _ _ ~ _
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78 DIET, NUTRITION, AND CANCER
In other studies, clofibrate, a hypolipidemic agent, or a placebo was
administered to more than 10,000 volunteers between 30 to 54 years of age
whose serum cholesterol levels were in the top fertile (committee on Prin-
ciple Investigators, 1978~. The total mortality from causes other than
ischemic heart disease was substantially higher in the clofibrate group:
there was a disproportionately large number of neoplasms of the gastroin-
testinal tract and a few more neoplasms in the respiratory tract. How-
ever, there were too few cancer deaths to demonstrate a statisticially
significant difference among the test groups.
In another study of the relationship between colon cancer and serum
cholesterol, Rose _ al. (1974) observed that the initial levels of serum
cholesterol in colon cancer patients were lower than expected. They also
reported that serum cholesterol levels were higher in patients with cancer
of the stomach, pancreas, liver, bile ducts, and rectum than in the con-
trols. Bjelke (1974) reported a similar correlation between colon cancer
and low levels of serum cholesterol. Nydegger and Butler (1972) examined
total serum cholesterol levels in 186 controls and 122 subjects with
malignant tumors. Their data also generally showed lower cholesterol
levels in the cancer patients.
Beaglehole et al. (1980) studied the relationship between serum
cholesterol concentration and mortality in New Zealand Maoris over a
period of 11 years. They found significant inverse relationships be-
tween serum cholesterol concentrations and cancer mortality.
In a 7.5-year follow-up study of London civil servants, Rose and
Shipley (1980) observed that mortality from cancer at all sites was
associated with a progressive decline in plasma cholesterol levels.
These investigators grouped cancer deaths into those that occurred
less than 2 years after the subjects entered the study and those that
occurred from 2 to 7.5 years afterward. For the group in which deaths
occurred within 2 years, the age-adjusted mortality rate for those with
the lowest plasma cholesterol levels was more than double the rate for
those with the highest levels. However, cancer deaths among those
followed for longer than 2 years occurred at the same rate, regardless
of plasma cholesterol level at entry into the study. The investigators
concluded that the decline in cholesterol levels was probably a meta-
bolic consequence of cancer, which, while unsuspected, was present when
the subjects entered the study.
In more than 5,000 subjects studied for 24 years in the Framingham
Heart Study (Williams et al., 1981), an inverse relationship between
serum cholesterol levels and cancer of the colon and other sites was ob-
served in men but not in women.
Kark et al. (1980) related serum cholesterol levels to cancer inci-
dence in more than 3,000 individuals followed for as long as 14 years in
Evans County, Georgia. Patients diagnosed as having cancer at any site
at least 1 year following entry into the study had had entry serum cho-
lesterol levels significantly lower than those in the noncancer patients.
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Lipids (Fats and Cholestero1) 79
This association was the same for black and white females and for black
and white males, but was stronger in males of both races. The possibility
that the presence of cancer may have been responsible for the lower serum
cholesterol levels was investigated. Patients were categorized into
three groups, depending on when evidence of cancer was first observed
after entry into the study: within 1 year, from 1 to 6 years, and from 7
to 13 years. Initial serum cholesterol levels were higher in the first
group than in the other two groups, but no differences were noted between
the latter groups. Kark and colleagues also observed little difference
in cholesterol levels in cases and controls when various cancer sites
were grouped together. However, they did report low serum cholesterol
levels in lung cancer- patients, whereas Stamler et al. (1968) observed
that serum cholesterol levels were higher in lung cancer cases than in
controls. A study conducted in Norway indicated that there was no over-
all relationship between serum cholesterol levels and total cancer inci-
dence (Westlund and Nicolaysen, 1972~.
In the Honolulu Heart Study, 598 deaths were observed in 7,961 men
whose cholesterol levels had been determined and who were followed for 9
years (Kagan et al., 1981~. The baseline serum cholesterol levels were
directly associated with mortality from coronary heart disease but in-
versely associated with total cancer mortality, mortality from cancers of
the esophagus, colon, liver, and lung, and malignancies of the lymphatic
and hematopoietic systems.
In Yugoslavia, Kozarevic et al. (1981) related baseline serum choles-
terol levels to mortality in 11,121 males over a 7-year period. The in-
verse association between cancer deaths and serum cholesterol levels was
not statistically significant.
In the Puerto Rico Heart Health Programme, 9,824 men were followed
for 8 years (Garcia-Palmieri et al., 1981~. Serum cholesterol levels mea-
sured at the first examination were found to vary inversely with subse-
quent mortality from cancer.
Peterson _ al. (1981) followed 10,000 men in Sweden for a mean of
2.5 years. They found that deaths from neoplastic disease and other
noncoronary heart disease peaked at low levels of serum cholesterol.
In contrast, serum cholesterol was not associated with overall risk
of death from cancer in three epidemiological studies of Chicago men
(Dyer et al., 1981~. When cancer deaths were evaluated by site, there
was a significant inverse association between serum cholesterol and
deaths from sarcoma, leukemia, and Hodgkin's disease in the nearly 2,000
men studied for 17 years, but not for deaths from lung cancer, colorectal
cancer, cancer of the oral cavity, pancreatic cancer, or all other can-
cers combined. There was, however, a suggestion of a direct association
for breast cancer in women.
These studies have been assessed by Lilienfeld (1981) and by others,
who concluded that the observed inverse correlations do not substantiate
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80 DIET, NUTRITION, AND CANCER
any direct cause-and-effect relationship between low blood cholesterol
levels and cancer.
Only one case-control study has specifically evaluated serum choles-
terol levels in cases of colon cancer and matched controls (Miller et
_., 1981~. In 133 pairs matched by age and sex, serum cholesterol
levels were lower for cases than for controls. However, following
stratification by tumor stage, significant differences in cholesterol
levels persisted only between cases with advanced tumors and controls.
Furthermore, only women, not men, had significantly lower serum choles-
terol levels with advancing disease. The lack of an association in early
disease supports the concept that low serum cholesterol levels observed
in colon cancer patients may be the result of a metabolic change accom-
panying tumor growth and may not necessarily precede tumor formation.
Miller et al. (1978) studied the association of dietary levels of
cholesterol and breast cancer. They found no significant differences
in estimated cholesterol consumption between cases and controls. In
another case-control study, the same group found that cholesterol intake
for males with rectal cancer and females with colon and rectal cancer was
higher than for controls (Jain et al., 1980~. Although the relative risk
for dietary cholesterol was significant at higher intakes for all male
and female cases, compared to all controls, it was substantially less
than the estimates of risk for other nutrients associated with intake of
fat, especially saturated fat.
There is an apparent conflict in the evidence, i.e., that an in-
creased risk of cancer of the colon and other sites has been associated
not only with dietary cholesterol (and simultaneous intake of other,
possibly more relevant lipid components) but also with very low serum
cholesterol levels. A possible explanation might be that a high intake
of dietary fat (and/or cholesterol) by persons whose metabolism maintains
low serum cholesterol results in reduced biosynthesis of cholesterol and
a high rate of excretion for cholesterol breakdown products in the
intestine (tin and Connor, 1980~. These breakdown products could serve
as substrates for the intraluminal production of carcinogens by intes-
tinal bacteria (Hill et al., 1971~. However, in metabolic studies con-
ducted in hospital wails, low serum cholesterol is usually accompanied by
excretion of low levels of bile acid. This observation is not compatible
with the mechanisms normally proposed for the carcinogenic effect of
dietary lipids.
In summary, data pertaining to the association between serum
cholesterol levels and total cancer incidence and mortality are incon-
sistent. An inverse correlation between serum cholesterol levels and
colon cancer in men has been noted in some studies, but not in all. It
is not clear whether lower than normal serum cholesterol levels are the
cause, or whether they reflect the metabolic consequences, of cancer.
Thus, the data are inconclusive and do not point to a causal relationship
between low cholesterol levels and risk of colon cancer. However, since
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Lipids (Fats and Cholesterop Sl
they do suggest that low serum cholesterol levels may be a clue to some
unknown factor, possibly something that is transported in the low density
lipoprotein fraction of serum, these data and future findings should be
examined carefully.
RELATIONSHIP OF FECAL STEROID EXCRETION TO BOWEL CARCINOGENESIS
The possibility that metabolites in the colon could provide a clue to
the presence of malignancy has stimulated a number of investigators to
study the level and spectrum of steroids in the feces of populations at
low or high risk for colon cancer, as well as of animals fed colon car-
cinogens together with various dietary regimens. The amounts of neutral
and acidic fecal steroids correspond to the level of fat intake. How-
ever, studies of the ratios of primary to secondary bile acids or the
ratio of cholesterol to its metabolic products (i.e., coprostanol and
coprostanone) have revealed no significant differences among the popula-
tions studied (Moskovitz et al., i979; Mower et al., 1979; Reddy, 1979~.
Recent comparisons of high risk and low risk populations, e.g., three
socioeconomic groups in Hong Kong (Hill et al., 1979) and Finns and New
Yorkers (Ready, 1979), suggest that the concentration of bile acids is
elevated in feces of the groups that are at higher risk.
Pioneering efforts by Hill and his colleagues (1971) pointed to an
association between rates of mortality from colon cancer and fecal
excretion of bile acids as well as the fecal degradation of cholesterol
and its metabolizes. They revived an earlier concept, based on struc-
tural and steric similarities, that bile acids might be transformed to
the carcinogen 3-methylcholanthrene by anaerobic gut bacteria. In the
studies leading to these earlier theories, deoxycholic acid was converted
chemically to 3~ethylcholanthrene by Wieland and Dane (1933) and by Cook
and Haslewood (1933~. Later, Fieser and Newman (1935) derived the same
carcinogen from cholic acid. The chemical steps used in these studies
were all reactions known to occur naturally, i.e., oxidation, hydrogena-
tion, cyclization, and dehydrogenation, although laboratory conditions
for the synthesis did not reproduce normally encountered biological
conditions.
Through the efforts of Hill, Reddy, Mastromarino, Narisawa, Nigro,
their coworkers, and others, the concept has evolved that fecal bile
acids and metabolizes of cholesterol may function as cocarcinogens,
carcinogens, or promoters in tumorigenesis of the large bowel (Hill et
al., 1971; Mastromarino et al., 1976; Narisawa et al., 1974; Nigro et
al., 1973; Reddy and Wynder, 1973; Reddy et al., 1977a). To date, how-
ever, no active carcinogen derived from bile acids has been isolated
from human or animal feces.
Reddy_al. (1977a) demonstrated that a fourfold increase in dietary
fat (from 5% to 20%) given to rats increased the 24-hour fecal excretion
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82 DIET, NUTRITION, AND CANCER
of neutral and acid sterols by 30% to 40% (based on body weight). Bac-
terial conversion of primary to secondary bile acids occurred more exten-
sively in rats fed the high fat diet than in those fed the low fat diet.
The possibility that bile acids may have tumor-promoting effects is
supported to some extent by the finding that bile acids affect cell ki-
netics in the intestinal epithelium. Diversion of biliary and pancrea-
tic secretions from the intestine decreases DNA synthesis and cell pro-
liferation (Fry and Staffeldt, 1964; Ranken et al., 1971; Roy et al.,
1975), whereas the administration of secondary bile acids increases cell
proliferation in liver bile ducts and the biliary tract epithelium
(Bagheri _ al., 1978~. Inhibition of DNA synthesis and cell prolifer-
ation has also been observed in the rat colon following biliary diversion
(Deschner and Raicht, 1979~.
Possible promotional effects of bile acids on bowel tumorigenesis
were suggested in studies initiated by Narisawa et al. (1974) and com-
pleted, with a large sampling of bile acids, by Redly and colleagues
(see review by Reddy _ al., 1980~. In these studies, N-methyl-N'-
nitro-N-nitrosoguanidine (MNNG), which is a direct-acting carcinogen,
was administered intrarectally to conventional or germfree rats for 2
weeks. During the subsequent 16 weeks, 20 mg doses of sodium cholate,
sodium chenodeoxycholate, or sodium lithocholate in 0.5 ml of peanut oil
were administered intrarectally to rats 3 times a week. No tumors were
detected in the control groups. The total number of large bowel tumors
in each of the conventional and germfree rats given intrarectal instilla-
tions of bile salts was greater than in rats given MNNG without bile
salts. These data also suggest that gut microflora was not required
for the effect of bile acids to be manifested. In this study, the
quantity of bile salts administered intrarectally was approximately 20
to 60 times higher than that normally excreted in the feces during a
24-hour period. Perhaps more importantly, the instillations at levels
of approximately 100 mM were at least 10 times higher than the normal
concentrations of these salts within the lumen of the bowel.
Palmer (1979) observed that bile salts interact readily with mem-
branes from artificial liposomes, bacteria, and mammalian cells. The
well-studied cytotoxic effects of bile salts are invariably preceded by
alterations in membrane permeability in red blood cells, in a variety of
tissues, and in mucosal cells of both the large and the small intestine
(Dawson and Isselbacher, 1960; Dietschy, 1967; Hoffman, 1967~. In one
study, the effects of these salts upon permeability (and presumably
cytotoxicity) in the gut were minimized when conjugated bile salts were
added to the unconjugated bile salts in sufficiently high concentrations
(Low-Beer _ al., 1970~. Thus, it cannot be determined whether the
effects of intrarectally instilled unconjugated bile salts demonstrated
classic tumor promotional activity or resulted from nonspecific damage
and repair activity associated with increased cellular proliferation of
the colonic mucosa induced by the high intraluminal concentration of the
salts.
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Lipids (Fats and Cholesterol) 83
Cohen and associates studied the effect of bile acid on colon tumors
induced by nitrosomethylurea (NMU) by feeding rats lab chow pellets with
and without added bile acid. They observed that 0.2% cholic acid (Cohen
et al., 1978), but not chenodeoxycholic acid (Raicht et al., 1975), in-
creased the number of NMU-induced colon tumors, as compared to the num-
ber of tumors in rats fed nonsupplemented pellets. In the dimethylhydra-
zine (DMH) model, no effect on colon tumorigenesis was observed in rats
fed 0.3% cholic acid in a semisynthetic diet (Broitman, 1981~.
Evidence that increased quantities of bile acids in the colonic lumen
were associated with an increase in azoxymethane (AOM)-induced colon
tumorigenesis in rats was provided by Chomchai et al. (1974~. Williamson
et al. (1979) showed that bile initiated prompt ileal hyperplasia in rats
following intestinal resection with diversion of the pancreatic and bil-
iarv ducts to the terminal ileum, i.e., pancreatobiliary diversion.
Feeding cholestyramine to rats given AOM for tumor induction increased
the average number of tumors in the large bowel but not in the small bowel
(Nigro et al., 1973, 1977~. Vahouny et al. (1981) demonstrated that in-
tralumina i nfusion of 165 AM of chol~c, deoxycholic, and chenodeoxycholic
acids 1:1:1 twice daily for 5 days resulted in severe topological changes
in the colonic mucosa.
Thus, the enhancement of tumorigenesis observed at high concentra-
tions of bile acids may be related to nonspecific effects of tissue
injury. Tumor-enhancing effects of nonspecific injury have been attrib-
uted to increased cellular proliferation, which accompanies inflammation
and repair (Ryser, 1971~.
EXPERIMENTAL EVIDENCE
-
The first demonstration that dietary fat could influence tumorigene-
sis was reported by Watson and Mellanby (1930~. Most of these studies
were conducted by increasing the level of dietary fat, which also led to
an increase in the total intake of calories. Addition of 12.5% to 25.0%
butter to a basal (3% fat) diet given to coal-tar-treated mice increased
the incidence of skin tumors from 34% to 57%. Similarly, Lavik and
Baumann (1941, 1943), who administered 3-methylcholanthrene topically to
mice found that a basal diet, when supplemented with 15% fat (shortening),
increased the yield of skin tumors from 12% to 83%. Fat was especially
effective when fed 6 to 12 weeks after treatment with a carcinogen. Com-
paring diets containing 10% corn oil, 10% coconut oil, or 10% lard for
their ability to enhance tumors, these investigators observed a minor
effect of unsaturation: the incidence of tumors at 5 months was 33% (for
control diets), 61% (for added lard diets), 66% (for added coconut oil
diets), and 76% (for added corn oil diets).
Mammary Tumors
Tannenbaum (1942) demonstrated that dietary fat enhanced the develop-
ment of either chemically or spontaneously induced mammary tumors in mice.
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Lipids (Fats and Cholesterop 95
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5 -33
Representative terms from entire chapter:
serum cholesterol
