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1487
Lack of Promotion of Colon Carcinogenesis by
High-Oleic Safflower Oil
Masazumi Takeshita, M.D.1
Hiroshi Ueda, Ph.D.2
Komei Shirabe, M.D.3
Yasunori Higuchi, M.D.4
Satoshi Yoshida, Ph.D.5
BACKGROUND. The nonpromoting effect of olive oil on colon carcinogenesis has
been attributed to its high oleic acid content, whereas a positive association of
monounsaturated fat in beef tallow with colon tumors has been reported. The
effect of constituents other than fatty acids could not be neglected in these experiments. In order to minimize the effects of minor constituents in the oils, the
1
Department of Biochemistry, Oita Medical University School of Medicine, Oita, Japan.
2
Department of Biochemistry, Institute for Developmental Research, Aichi Service Center, Aichi, Japan.
3
Department of Biochemistry, Oita Medical University School of Medicine, Oita, Japan.
4
Department of Pathology, Oita Medical University School of Medicine, Oita, Japan.
5
Research Laboratory Center, Oita Medical University School of Medicine, Oita, Japan.
authors compared conventional safflower oil with oil from a mutant strain of
safflower that is rich in oleic acid.
METHODS. ICR mice were treated with 1,2-dimethylhydrazine (DMH, 20 mg/kg
body weight every week for 12 weeks) and then were fed either a high-fat diet
(23.5% by weight), containing safflower oil (HF-LA) or high-oleic safflower oil (HFOA), or a low-fat diet (5% by weight), containing safflower oil (LF-LA) or higholeic safflower oil (LF-OA). The test diets were continued until termination of the
experiment at 30 weeks after the first administration of DMH. Fatty acid composition of colon phospholipids was determined by gas-liquid chromatography-mass
spectrometry.
RESULTS. Tumor multiplicity in animals fed the HF-OA diet was indistinguishable
from that in animals fed LF-LA or LF-OA. In contrast, animals fed the HF-LA diet
had a significantly higher incidence of colon tumors (mostly adenocarcinomas)
than the other groups. Fatty acid profiles of colon phospholipids reflected those
of the diet. Animals fed a HF-LA diet showed a marked decrease of nervonic acid
(C24:1 , n-9) in the colon sphingomyelin.
CONCLUSIONS. These data indicate that oleic acid does not enhance DMH-induced
colon carcinogenesis in mice, even when they are fed a high-fat diet. Cancer 1997;
79:1487–93. q 1997 American Cancer Society.
KEYWORDS: colonic neoplasm, fatty acid, oleic acid, dimethylhydrazine, phospholipid, sphingomyelin.
Presented in part at the International Conference
on Food Factors: Chemistry and Cancer Prevention,
Hamamatsu, Japan, December 10–15, 1995.
Supported in part by Grants-in-Aid (Nos. 05258216
and 06280228) from the Ministry of Education,
Science, Sports and Culture of Japan.
The authors thank Mr. Atsushi Ohara of the Nisshin
Oil Mills, Ltd. for donating safflower oil and higholeic safflower oil; Toshitsugu Yubisui, Ph.D., Department of Biology, Kochi University, Faculty of
Science, for his valuable discussions regarding this
report; Miss Mami Sakurai for her excellent technical assistance and preparation of the manuscript;
and Dr. D. E. Hultquist, Department of Biological
Chemistry, the University of Michigan Medical
E
pidemiologic and laboratory animal studies have indicated that
the amount and type of fat in the diet influence the incidence of
colon carcinoma and mortality rates of patients with this disease.1,2
In the early 1950s, Japan was one of the countries with the lowest
incidence of carcinogenesis in the large intestine. Recently, however
the rate of colon carcinoma incidence has been rising in Japan. This
is mainly attributed to a shift to a Western-style diet and to an increase
in fat consumption.1 The Japanese diet has been progressively chang-
School, for reviewing the English in the manuscript.
Animals were maintained according to the standards set forth in the Guidelines for the Care
and Use of Laboratory Animals of Oita Medical
University.
q 1997 American Cancer Society
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03-17-97 10:12:33
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W: Cancer
Address for reprints: Masazumi Takeshita, M.D.,
Department of Biochemistry, Oita Medical University School of Medicine, Hasama-machi, Oita
879-55, Japan.
Received December 3, 1996; accepted December
30, 1996.
1488
CANCER April 15, 1997 / Volume 79 / Number 8
ing. The amount of fat in the diet reached approximately 25% of total calories in 1987, and it continues
to rise. Total fat intake in Mediterranean countries is
about 34% of total calories in 1980, which is between
that in Japan (24%) and in the U.S. (43%).1,3
In Southern Italy, the occurrences of colorectal,
breast, and ovarian carcinoma are significantly less
frequent than in Northern Italy.3 A more recent epidemiologic study indicated an inverse relation between
olive oil intake and the risk of breast carcinoma in
Spain.4 Dietary olive oil, which is rich in oleic acid, is
very common in Southern Italy, and a high monoenoic
fatty acid content is found in the red cell membranes
of individuals from Southern Italy compared with individuals in U.S. and Finland.5
It has been reported that diets containing high
levels of safflower oil, which is rich in linoleic acid,
enhance the development of experimental mammary
carcinogenesis,6 whereas diets containing high levels
of olive oil, with its high content of oleic acid, do not
promote mammary carcinogenesis.7 The incidence of
azoxymethane-induced colon tumors was increased in
rats fed diets with high corn oil or safflower oil content,
whereas the diet with high olive oil content had no
promoting effect on colon tumor incidence.8 The nonpromoting effect of olive oil has been attributed to its
high content of oleic acid. However, the possible effect
of minor constituents, such as squalene, carotenoids,
or b-sitosterol, could not be neglected. Squalene,
which is present in considerable amounts in olive oil,
has been shown to potentiate the effects of anticancer
agents.9 Contrary to these results, Linder reported a
linear association between dietary monounsaturated
fat consumed as beef tallow and the incidence of colon
tumors.10 In addition, the effect of minor constituent(s) on the metabolism of fat and carcinogenesis
could not be neglected in the current study.
This study was designed to test whether monounsaturated fatty acid is responsible for the promotion
of carcinoma of the large intestine. To minimize the
effects of minor constituents in the oils, we examined
the effect of the dietary fatty acid on 1,2-dimethylhydrazine (DMH) – induced carcinogenesis in mice, using
a conventional safflower oil as well as a mutant strain
of safflower oil in which oleic acid is the dominant
fatty acid rather than linoleic acid.
MATERIALS AND METHODS
Chemicals, Animals, and Diets
All semipurified dietary ingredients were from Oriental
Yeast Co. Ltd., Chiba, Japan. Safflower oil and higholeic safflower oil were donated by the Nisshin Oil
Mills, Ltd., Yokohama, Japan. DMH dihydrochloride
was provided by Nacalai Tesque Inc., Kyoto, Japan.
A total of 124 female ICR mice (a strain derived
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03-17-97 10:12:33
TABLE 1
Composition of Experimental Diets
Percentages of ingredients
Ingredients
Low-fat dieta
High-fat dietb
Casein, vitamin-free
a-Corn starchc
b-Corn starch
Dextrose
Fat
DL-methionined
Choline bitartrate
Cellulose powder
Mineral mix
Vitamin mix
20.0
10.0
42.0
13.0
5.0
0.3
0.2
5.0
1.0
3.5
23.5
10.0
22.9
8.3
23.52
0.35
0.24
5.9
1.18
4.11
a
These diets were prepared according to criteria of the American Institute of Nutrition Standard
Reference Diet11,12 with the modification of varying the source of carbohydrate.
b
Additional fat (safflower oil or high-oleic safflower oil) was added at the expense of b-corn starch
and dextrose. The composition of high-fat diets was adjusted so that the intake of the other ingredients
and calories in animals in the different dietary groups was the same.2
c
a-Corn starch (10%) was included to make a pelleted laboratory diet. For pelleting, the amount of
oil in the diets was limited to 12%. To increase fat content to 23.52%, additional oil was added after
pelleting.
d
DL denotes racemic modification.
from Swiss mice) 4 weeks of age were purchased from
Seiwa Experimental Animals Ltd., Fukuoka, Japan, and
maintained on a standard CE2 diet (Nihon Clea Co.,
Tokyo) with water given ad libitum. They were randomly distributed by weight into 4 dietary groups of
31 animals each. Each dietary group was divided into
subgroups of 25 DMH-treated and 6 vehicle-treated
animals and housed 5 (DMH-treated) and 3 (vehicletreated) to a plastic cage with sterilized wood chip
bedding. The animals were maintained in an animal
holding room furnished with air filters under controlled environmental conditions, with 12-hour lightdark cycles and at a temperature of 23 7C.
The composition of the experimental semipurified
diets is shown in Table 1. The low-fat diet (5% fat by
weight) mimicked the average Japanese diet as it was
in 1960s. The high-fat diet (23.5% fat by weight) mimicked the average American diet today. The compositions of the high- and low-fat diets were adjusted so
that the animals in all dietary groups would consume
the same number of calories and the same amounts
of protein, vitamins, minerals, and fiber.11,12 The experimental diets of 5% oil were prepared and solidified
at Oriental Yeast Co. Ltd. In contrast, a diet of 23.52%
oil could not be solidified because of technical difficulties, so 12% oil diets were first prepared by the
manufacturer, then divided into small portions, and
oil was added to the 23.5% fat diets 3 times a week.
The atmosphere above the experimental diets was exchanged with N2 gas and stored at 020 7C until use.
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1489
TABLE 2
Body Weight of Female Mice Treated with DMH and Fed the Experimental Dietsa
Body weight (g)
Diet groupb
Initial weight
(Week 0)
Week 2
Week 5
Week 10
Week 15
Week 27
Week 33
(At termination)
LF-LA
HF-LA
LF-OA
HF-OA
25.4 { 1.1c
25.7 { 1.3
25.7 { 1.3
26.1 { 1.3
27.9 { 1.8
28.1 { 2.3
28.2 { 2.2
28.6 { 2.2
29.1 { 2.5
27.3 { 3.7
28.5 { 2.2
28.9 { 2.5
28.2 { 2.7
28.4 { 3.3
28.6 { 3.0
30.5 { 3.7
31.0 { 2.5
30.4 { 3.3
30.2 { 2.9
31.2 { 3.7
33.7 { 4.2
37.4 { 5.7
33.8 { 4.4
37.8 { 5.2
35.3 { 5.3
38.4 { 6.2
33.9 { 5.4
37.0 { 6.1
DMH: 1,2 dimethylhydrazine; LF: low-fat; HF: high-fat; LA: safflower oil (not high in oleic acid); HA: safflower oil high in oleic acid.
a
Analysis of variance (ANOVA) with repeated measures, not significant.
b
Number of DMH-treated mice in each group was 25.
c
Mean standard deviation.
Those diets stored in the cold were analyzed for peroxides with thiobarbituric acid tests.13 Thiobarbituric
acid tests for lipid peroxides were essentially negative
during the experiment. Using metabolism cages, food
consumption was measured in 5 animals from each
dietary group for a period of 1 week after the animals
had been on experimental diets for 8, 16, and 24 weeks.
Carcinogenesis Experiment
At 8 weeks of age, animals intended for DMH treatment in each group were given 12 weekly intraperitoneal injections of DMH at a dose of 20 mg/kg. Prior
to injection, the DMH was dissolved in 1mM ethylenediamine tetraacetic acid (EDTA), and the pH was
raised to 6.5 with sodium bicarbonate. The animals
for vehicle treatment were given the same volume of
1 mM EDTA, pH 6.5. One week before the first injection of DMH, groups of animals that had been on a
standard CE2 diet were transferred to high-fat diets,
containing either (by weight) 23.52% safflower oil (45%
of total calories, designated as HF-LA) or 23.52% higholeic safflower oil (HF-OA), or low-fat diets, containing
either 5% safflower oil (12% of total calories, LF-LA)
or 5% high-oleic safflower oil (LF-OA). All animals
were fed the experimental diets until termination of
the experiment. Body weights were measured weekly
when the animals were 7 weeks (Week 0) to 15 weeks
of age, and every 5 to 7 weeks thereafter, as indicated
in Table 2, until the termination of the experiment.
Food consumption was measured for a period of 1
week after every 5 weeks that the animals were on
experimental diets. The experiment was terminated 30
weeks after the first treatment of DMH. Both DMHtreated and vehicle-treated animals were sacrificed by
cervical dislocation after etherization. At autopsy, all
organs, including intestines, were macroscopically examined for tumors. Tissues were fixed in 20% formalin
neutral-buffer-methanol solution (formaldehyde 8%,
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03-17-97 10:12:33
methanol 20%). Paraffin embedded tissue sections
were stained with hematoxylin and eosin and examined histologically for tumor types.14
Lipid Analysis
The fatty acid compositions of safflower and high-oleic
safflower oils were analyzed by gas-liquid chromatography after methylation with 5% HCl in methanol. Safflower
oil contained approximately 7% palmitic acid (C16:0), 2%
stearic acid (C18:0), 16.5% oleic acid (C18:1 , n-9), and 73%
linoleic acid (C18:2 , n-6). High-oleic safflower oil contained
approximately 6% palmitic acid, 2% stearic acid, 75% oleic
acid, and 15% linoleic acid. Sterol fraction was prepared
as unsaponifiable matter by an usual saponification
method and analyzed by capillary gas-liquid chromatography. Tocopherols were analyzed by high-performance
liquid chromatography. For the assay of squalene, hydrocarbon fraction was separated from the oils by column
chromatography on silica gel and analyzed by capillary
gas-liquid chromatography. Both oils contained approximately 0.23% sterols; sitosterol was the major sterol, tocopherols (mostly a-tocopherol) was present at 390 parts
per million, and traces of squalene were present. For the
analysis of tissue lipids, colonic mucosa removed from
DMH-treated mice were homogenized. Total lipids in the
homogenates were extracted by the method of Bligh and
Dyer15 and analyzed by the method described by Yamamoto et al.16 Briefly, the lipids were separated by thinlayer chromatography on silica gel plates (Merck 60,
Darmstadt, Germany) using diethylether/acetic acid (100/
0.5) as the developing solvent. The fatty acid composition
in the phospholipid fractions was analyzed by gas-liquid
chromatography-mass spectrography after methylation
with 5% HCl in methanol.
Statistical Analysis
The tumor data were analyzed with the chi-square
test and Fisher’s exact test. Weight gain data for each
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CANCER April 15, 1997 / Volume 79 / Number 8
TABLE 3
DMH-Induced Colonic Tumors in ICR Fed Diets Containing High and Low Amounts of Safflower Oil or High-Oleic Safflower Oil
Tumor incidence (animals with colonic tumors)
Tumor multiplicity (colonic tumors/animal)
Diet group
Total no. of
animals at risk
Total a
Adenocarcinoma
Squamous cell
carcinoma
Total
Adenocarcinoma
Squamous cell
carcinoma
HF-LA
HF-OA
LF-LA
LF-OA
25
25
25
25
18(72)b
3(12)d
4(16)d
3(12)d
15(60)
3(12)d
4(16)d
3(12)d
3(12)
0
0
0
1.20 { 1.15c
0.12 { 0.33d
0.16 { 0.37d
0.12 { 0.33d
1.08 { 1.22
0.12 { 0.33d
0.16 { 0.37d
0.12 { 0.33d
0.12 { 0.33
0
0
0
DMH: 1,2 dimethylhydrazine; LF: low-fat; HF: high-fat; LA: safflower oil (not high in oleic acid); HA: safflower oil high in oleic acid.
a
Total represents mice with adenocarcinoma and/or squamous cell carcinoma.
b
Numbers in parentheses are percentages of animals with tumors.
c
Mean { standard deviation.
d
Means in the same column that do not share a common superscript are significantly different at P õ 0.001 (chi-square test and Fisher’s exact test).
treatment group were analyzed by using a program for
analysis of variance (ANOVA) with repeated measures.
Significant differences in the values of fatty acids between various dietary groups were analyzed by ANOVA
and Student’s t test.
RESULTS
Animal Weight Gain and Food Consumption
Body weights of animals fed the LF-LA, HF-LA, LFOA, and HF-OA diets were comparable throughout the
experimental period (Table 2). Average food consumption measured throughout the experiments indicated
that the animals fed the LF-LA and LF-OA diets consumed 12 – 14% more food than those fed the HF-LA
and HF-OA diets. There were essentially no differences
in food consumption between animals on the LF-FA
and LF-OA diets or between those on the HF-LA and
HF-OA diets.
Tumor Incidence and Multiplicity
Table 3 summarizes the DMH-induced colonic tumor
incidence (number of animals with tumors) and tumor
multiplicity (number of tumors/animal) in animals fed
the various diets. The tumors in large intestines were
mostly adenocarcinomas; however, a few tumors in
animals given a high safflower oil diet were histologically identified as squamous cell carcinomas, which
were seen near and around the anus. A few liver angiosarcomas were seen in the groups given HF-LA (4 animals), HF-OA (2 animals), and LF-OA (2 animals). The
incidence of carcinomas was significantly higher in
animals fed the HF-LA diet than in animals fed the
HF-OA, LF-OA, and LF-LA diets. The multiplicity of
large intestine carcinomas was also significantly
higher in animals fed the HF-LA diet than in animals
fed the other diets. No significant difference was observed in tumor incidence and multiplicity between
/ 7b54$$1013
03-17-97 10:12:33
FIGURE 1.
Fatty acid composition of phospholipid from the colonic
mucosa of DMH-treated mice is shown. The tissues of each diet group
were homogenized, extracted, and analyzed for the fatty acid composition
of the total phospholipid as described in the text. Bars correspond to the
HF-LA (solid bar), HF-OA (open bar), LF-LA (striped bar), and LF-OA
(dotted bar) diets. The data are given as the mean percentages of the total
amount of fatty acid present in the phospholipids; values of five experiments { standard error. HF: high-fat; LF: low-fat; LA: safflower oil (not
high in oleic acid), OA: safflower oil high in oleic acid. *P õ 0.01; †P õ
0.001; ‡P õ 0.0001.
the HF-OA dietary group and low-fat dietary groups.
There was no tumor generation in vehicle-treated
mice in any dietary group (data not shown).
Fatty Acid Composition in Phospholipids
The percentage compositions of fatty acids in colon
phospholipids are shown in Figure 1. The fatty acid
profile for each dietary group is reflected in the fatty
acid composition of the colon phospholipids. The dietary HF-LA caused a significant increase in linoleic
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1491
acid (P õ 0.0001 vs. the HF-OA, LF-OA, and LF-LA
diets), and oleic acid significantly increased in the HFOA and LF-OA dietary groups as compared with the
HF-LA dietary group. No difference in the content of
arachidonic acid (C20:4 , n-6) in colon tissue was observed among the four dietary groups. Fatty acid compositions of phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin are shown in Figure 2.
In phosphatidylcholine and phosphatidylethanolamine, dietary HF-LA caused a significant increase in linoleic acid as compared with HF-OA, LF-OA, and LF-LA
diets (Figs. 2A and 2B). Similar trends were observed
in phosphatidylinositol and phosphatidylserine (data
not shown). The most characteristic difference in the
fatty acid composition of sphingomyelin among dietary groups was that the nervonic acid (C24:1 , n-9)
was markedly decreased in the HF-LA dietary group
as compared with other dietary groups, and palmitic
acid (C16:0) was significantly increased in the HF-LA
dietary group as compared with the HF-OA and LFOA dietary groups. (Fig. 2C).
DISCUSSION
FIGURE 2. A–C. Fatty acid composition is shown of phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin from colonic mucosa
of DMH-treated mice. Bars correspond to the HF-LA (solid bar), HF-OA
(open bar), LF-LA (striped bar), and LF-OA (dotted bar) diets. The data
are given as the mean percentages of the total amount of fatty acid present
in the phospholipids; values of five experiments { standard error. HF:
high-fat; LF: low-fat; LA: safflower oil (not high in oleic acid); OA: safflower
oil high in oleic acid. *P õ 0.01; †P õ 0.001; ‡P õ 0.0001.
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The results of this study indicate that in mice fed the
HF-LA diet, which contained high levels of linoleic
acid, the incidence and multiplicity of DMH-induced
large intestinal tumors were significantly increased as
compared with the tumor incidence and multiplicity
in mice fed the HF-OA, LF-LA, or LF-OA diets. The
high-oleic safflower oil was prepared from a mutant
strain of safflower in which oleic acid is the dominant
fatty acid, whereas in conventional safflower oil linoleic acid predominates. Other components were not
different between these two oils. Thus, the effects of
tumorigenesis in these diet groups were most probably
due to from the difference in fatty acid composition,
especially that of oleic acid (C18:1 , n-9) and linoleic
acid (C18:2 , n-6).
It is generally accepted that fat in the diet influences the growth of colon tumors. However, not
all fats have the same effect. A number of experiments have indicated that fatty acid composition
of fat in the diet is one of the determining factors
in carcinogenesis. Reddy and Maeura8 reported that
high-fat diets containing safflower oil or corn oil
increased the incidence of colon tumors as compared with low-fat diets, whereas high-fat olive oil
diets did not increase colon tumor incidence. These
results are compatible with our results. However,
contradictory results have also appeared. Lindner10
reported using a different strain of mice in which
beef tallow increased the serum monounsaturated
fat and colon carcinoma incidence had a positive
association with the content of monounsaturated
fatty acid in the intestinal mucosa. The oleic acid
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CANCER April 15, 1997 / Volume 79 / Number 8
content of beef tallow (at most, 40% of the total fatty
acid) is not as high as that of high-oleic safflower
oil (76%). Although no purity description is given,
available beef tallow would be expected to include
some minor constituents. The association of beef
tallow with high carcinoma incidence might be
caused by other factor(s). A recent report indicated
that an elevated risk of cancer was associated with
beef, but specifically with red meat intake.17 Further
investigation will be needed to address these discrepancies.
The lack of enhancement of colonic carcinogenesis by n-3 fatty acids2,18 and the inhibition of
tumor development by indomethacin implicate
prostaglandin synthesis in this phenomenon.19,20
The Menhaden fish oil rich in n-3 fatty acids decreased arachidonic acid content in the tissues and
induced fewer colon adenocarcinomas than did the
diet containing a high-corn oil content that was rich
in n-6 fatty acids.21,22 In the current study, however,
no significant difference in the content of arachidonic acid, a precursor of prostaglandins, in the
colonic tissue was observed between diet groups
receiving high-linoleic and high-oleic safflower oil.
To rule out the possibility of participation of prostaglandins in large intestine carcinogenesis, we need
further studies, but the constancy of arachidonic
acid in the tissues of different diet groups does not
suggest the participation of prostaglandins.
In the same series of experiments, we also found
an increase of palmitic acid (C16:0) and a concomitant
decrease in nervonic acid (C24:1 , n-9) in the sphingomyelin of the large intestines of the HF-LA diet mice.
The metabolic conversion from palmitic acid to nervonic acid might have been inhibited by linoleic acid,
as suggested by the observation that the elongation of
fatty acids having lower unsaturation has been inhibited by those having higher unsaturation.23 In recent
experiments with cultured 3T3 cells, ras transformation altered the fatty acyl composition of sphingomyelin with a doubling of the nervonic acid and a substantial reduction in the amount of palmitic acid.24 It is of
interest to relate the fatty acid composition of sphingomyelin to large bowel tumorigenesis, since the sphingomyelin cycle and sphingosin have been thought to
mediate signal transduction.25 – 27
In conclusion, the results of tumor incidence and
multiplicity under conditions in which oleic acid accumulates in colon phospholipids indicate that oleic acid
does not enhance colon carcinogenesis, even when a
high-fat diet is consumed.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
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