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Suppressing effect of perilla oil on azoxymethane-induced foci
of colonic aberrant crypts in rats.
We have investigated the modulatory effect of dietary perilla oil
which is rich in the n-3 polyunsaturated fatty acid, alpha-linolenic
acid, on the development of azoxymethane (AOM)-induced colonic aberrant
crypt foci (ACF) in male F344 rats. Animals were given three weekly
subcutaneous injections of AOM (15 mg/kg body weight) to induce ACE.
The rats were fed a basal diet containing either 12% olive oil, 12%
safflower oil, 12% perilla oil, 6% perilla oil plus 6% olive oil,
or 3% perilla oil plus 9% olive oil for 5 weeks, starting 1 week before
the first dosing of AOM. All rats were sacrificed 2 weeks after the last AOM
injection. The amount of food consumed and body weight gain were identical among
every dietary group. The frequency of ACF was significantly lower in the rats
fed 12% perilla oil than in those fed 12% olive oil or 12% safflower oil (P < 0.01
and P < 0.05, respectively). The suppressive effect of perilla oil was dose-dependent,
as the number of ACF was 20.7, 40.7 and 47.4% of those of the 12% olive oil-fed
controls in rats fed 12% perilla oil, 6% perilla oil plus 6% olive oil and 3%
perilla oil plus 9% olive oil, respectively. Perilla oil significantly reduced
ras expression as well as the AgNORs count (cell proliferation biomarkers) in
the colonic mucosa, as compared with olive oil or safflower oil (P < 0.01,
respectively). Marked increases in n-3 polyunsaturated fatty acids in membrane
phospholipid fractions and decreased PGE2 levels were observed in colonic mucosa
of perilla oil-fed rats. These results suggest that perilla oil, even in small
amounts, suppresses the development of aberrant crypt foci, and is therefore
a possible preventive agent in the early stage of colon carcinogenesis.
Carcinogenesis. 1996 Jun; 17(6):
1291-6
Colon cancer prevention with a small amount
of dietary perilla oil high in alpha-linolenic acid in an animal model.
BACKGROUND. Epidemiologic and experimental studies suggest that dietary fish
oil and vegetable oil high in omega-3 polyunsaturated fatty acids (PUFAs) suppress
the risk of colon cancer. The optimal amount to prevent colon carcinogenesis
with perilla oil high in omega-3 PUFA alpha-linolenic acid in a 12% medium-fat
diet was investigated in female F344 rats. For comparison, safflower oil high
in omega-6 PUFA linoleic acid was used. METHODS. Thirty or 25 rats at 7 weeks
of age in each group received an intrarectal dose of 2 mg N-methyl-N-nitrosourea
3 times weekly in weeks 1 and 2 and were fed the diets with various levels
of perilla oil and safflower oil throughout the experiment. RESULTS. The incidence
of colon cancer at the termination of the experiment at week 35 was 40%, 48%
and 32% in the rats fed the diets with 3% perilla oil plus 9% safflower oil,
6% perilla oil plus 6% safflower oil, and 12% perilla oil plus 0% safflower
oil, respectively, whereas it was 67% in the rats fed the control diet with
0% perilla oil plus 12% safflower oil. The amount of diet consumed and the
body weight gain were identical in all of the dietary groups. The ratios of
omega-3 PUFA to omega-6 PUFA in the serum and the colonic mucosa at week 35
were increased in parallel to the increased intake of perilla oil. CONCLUSIONS.
The results suggest that a relatively small fraction of perilla oil, 25% of
total dietary fat, may provide an appreciable beneficial effect in lowering
the risk of colon cancer.
Cancer. 1994 Apr 15; 73(8): 2069-75
Synergistic suppression of
azoxymethane-induced foci of colonic aberrant crypts by the combination
of beta-carotene and perilla oil in rats.
The modulating effect of the combined dietary feeding of beta-carotene
and perilla oil, which is rich in alpha-linolenic acid, on the development
of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was
investigated in male F344 rats. Rats received oral administration
of beta-carotene (0, 50 or 200 mg/kg body weight/day) and fed a basal
diet containing either 12% olive oil, 3% perilla oil plus 9% olive
oil, or 12% perilla oil. A dose-dependent suppressive effect of perilla
oil was found. The numbers of ACF were 42.0 and 18.4% of those of
the 12% olive oil-fed controls in the rats fed 3% perilla oil plus
9% olive oil and 12% perilla oil, respectively. The development of
ACF was also reduced significantly by the addition of dietary beta-carotene
in each of the oil-fed groups (P < 0.05, respectively). The suppression
by the combination of beta-carotene and perilla oil was synergistic,
as the numbers of ACF were 12.9 and 8.9% of those of the 12% olive
oil-fed controls in beta-carotene-treated rats fed 3% perilla oil
plus 9% olive oil and 12% perilla oil, respectively. beta-carotene
plus perilla oil also suppressed the numbers of silver-stained nucleolar organizer
regions and the expression of ras mRNA in the colonic mucosa (cell proliferation
biomarkers). Following administration of beta-carotene, a significant increase
in the concentration of intact beta-carotene molecules was found in the colonic
mucosa, livers, and sera. However, no accumulation of retinoids was observed
in the colonic mucosa, suggesting that the inhibitory effect may not be related
to the provitamin A activity. These results suggest that the combination of
beta-carotene and perilla oil may be useful in the prevention of colon cancer.
Carcinogenesis.
1996 Sep; 17(9): 1897-901 Epidemiological evidence of relationships between dietary
polyunsaturated fatty acids and mortality in the multiple risk factor
intervention trial.
This evaluation of the Multiple Risk Factor Intervention Trial database investigated
the effects of dietary PUFA on disease outcomes that may relate to polyunsaturated
fatty acid (PUFA) biochemistry. The Multiple Risk Factor Intervention Trial
was a randomized clinical trial in coronary heart disease (CHD) primary prevention
involving 12,866 middle-aged men determined to be at high risk of CHD. They
were assigned to either a special intervention group or a usual care group
and returned to clinics on an annual basis for assessment of risk factor status.
Only data on the usual care men (n = 6,250) are presented, since the multi-intervention
effects on the special intervention group introduce considerable analytic complexities.
Mean PUFA intake estimates were calculated from four dietary recall interviews
at baseline and follow-up Years 1, 2, and 3 and estimates for PUFA were established
using absolute grams, percentage of total kilocalories, and ratios. Proportional
hazards regression analysis controlling for age, race and baseline diastolic
blood pressure, smoking, high and low density lipoprotein cholesterol levels,
and alcohol was used to analyze dietary PUFA intakes on 10.5-year mortality
rates. Results were more significant when PUFA were expressed as percentage
of total kilocalories. No significant associations with mortality were detected
for linoleic acid (18:2n-6), the predominant dietary PUFA.
Proc Soc Exp Biol Med . 1992 Jun; 200(2): 177-82
Dietary fat and risk of coronary heart disease in men: cohort
follow up study in the United States.
OBJECTIVE--To examine the association between fat intake and the incidence
of coronary heart disease in men of middle age and older. DESIGN--Cohort questionnaire
study of men followed up for six years from 1986. SETTING--The health professionals
follow up study in the United States . SUBJECTS--43 757 health professionals
aged 40 to 75 years free of diagnosed cardiovascular disease or diabetes in
1986. MAIN OUTCOME MEASURE--Incidence of acute myocardial infarction or coronary
death. RESULTS--During follow up 734 coronary events were documented, including
505 non-fatal myocardial infarctions and 229 deaths. After age and several
coronary risk factors were controlled for significant positive associations
were observed between intake of saturated fat and risk of coronary disease.
For men in the top versus the lowest fifth of saturated fat intake (median
= 14.8% v 5.7% of energy) the multivariate relative risk for myocardial infarction
was 1.22 (95% confidence interval 0.96 to 1.56) and for fatal coronary heart
disease was 2.21 (1.38 to 3.54). After adjustment for intake of fibre the risks
were 0.96 (0.73 to 1.27) and 1.72 (1.01 to 2.90), respectively. Positive associations
between intake of cholesterol and risk of coronary heart disease were similarly
attenuated after adjustment for fibre intake. Intake of linolenic acid was
inversely associated with risk of myocardial infarction; this association became
significant only after adjustment for non-dietary risk factors and was strengthened
after adjustment for total fat intake (relative risk 0.41 for a 1% increase
in energy, P for trend < 0.01). CONCLUSIONS--These data do not support the
strong association between intake of saturated fat and risk of coronary heart
disease suggested by international comparisons. They are compatible, however,
with the hypotheses that saturated fat and cholesterol intakes affect the risk
of coronary heart disease as predicted by their effects on blood cholesterol
concentration. They also support a specific preventive effect of linolenic
acid intake.
BMJ. 1996 Jul 13; 313(7049): 84-90
Dietary intake of alpha-linolenic acid and risk of fatal ischemic
heart disease among women.
BACKGROUND: Experimental studies in laboratory animals and humans
suggest that alpha-linolenic acid (18:3n-3) may reduce the risk of
arrhythmia. OBJECTIVE: The objective was to examine the association
between dietary intake of alpha-linolenic acid and risk of fatal ischemic
heart disease (IHD). DESIGN: This was a prospective cohort study.
The intake of alpha-linolenic acid was derived from a 116-item food-frequency
questionnaire completed in 1984 by 76283 women without previously
diagnosed cancer or cardiovascular disease. RESULTS: During 10 y of
follow-up, we documented 232 cases of fatal IHD and 597 cases of nonfatal
myocardial infarction. After adjustment for age, standard coronary
risk factors, and dietary intake of linoleic acid and other nutrients,
a higher intake of alpha-linolenic acid was associated with a lower
relative risk (RR) of fatal IHD; the RRs from the lowest to highest
quintiles were 1.0, 0.99, 0.90, 0.67, and 0.55 (95% CI: 0.32, 0.94;
P for trend = 0.01). For nonfatal myocardial infarction there was
only a modest, nonsignificant trend toward a reduced risk when extreme
quintiles were compared (RR: 0.85; 95% CI: 0.61, 1.19; P for trend
= 0.50). A higher intake of oil and vinegar salad dressing, an important
source of alpha-linolenic acid, was associated with reduced risk of
fatal IHD when women who consumed this food > or =5-6 times/wk
were compared with those who rarely consumed this food (RR: 0.46;
95% CI: 0.27, 0.76; P for trend = 0.001). CONCLUSIONS: This study
supports the hypothesis that a higher intake of alpha-linolenic acid
is protective against fatal IHD. Higher consumption of foods such
as oil-based salad dressing that provide polyunsaturated fats, including
alpha-linolenic acid, may reduce the risk of fatal IHD.
Am J Clin Nutr. 1999 May; 69(5):
890-7
Mediterranean alpha-linolenic acid-rich diet in secondary
prevention of coronary heart disease.
In a prospective, randomised single-blinded secondary prevention trial
we compared the effect of a Mediterranean alpha-linolenic acid-rich
diet to the usual post-infarct prudent diet. After a first myocardial
infarction, patients were randomly assigned to the experimental (n
= 302) or control group (n = 303). Patients were seen again 8 weeks
after randomisation, and each year for 5 years. The experimental group
consumed significantly less lipids, saturated fat, cholesterol, and
linoleic acid but more oleic and alpha-linolenic acids confirmed by
measurements in plasma. Serum lipids, blood pressure, and body mass
index remained similar in the 2 groups. In the experimental group,
plasma levels of albumin, vitamin E, and vitamin C were increased,
and granulocyte count decreased. After a mean follow up of 27 months,
there were 16 cardiac deaths in the control and 3 in the experimental
group; 17 non-fatal myocardial infarction in the control and 5 in the
experimental groups: a risk ratio for these two main endpoints combined
of 0.27 (95% CI 0.12-0.59, p = 0.001) after adjustment for prognostic variables.
Overall mortality was 20 in the control, 8 in the experimental group, an
adjusted risk ratio of 0.30 (95% CI 0.11-0.82, p = 0.02). An alpha-linolenic
acid-rich Mediterranean diet seems to be more efficient than presently
used diets in the secondary prevention of coronary events and death. Lancet. 1994 Jun 11; 343(8911): 1454-9
Replacement of linoleic acid with alpha-linolenic acid does
not alter blood lipids in normolipidaemic men.
The effect of partial dietary
replacement of linoleic acid (18:2n-6; linoleic acid-rich diet) with
alpha-linolenic acid (18:3n-3; alpha-linolenic acid-rich diet) on plasma
lipids was investigated in twenty-nine healthy young men. After a 2-week
stabilization period subjects were randomly assigned to either the alpha-linolenic
acid-rich diet group (n 15), receiving a mean of 10.1 g of alpha-linolenic
acid and 12.1 g of linoleic acid/d, or the linoleic acid-rich diet group
(n 14), receiving a mean of 1.0 g of alpha-linolenic acid and 21.0 g
of linoleic acid/d, for a 6-week test period. Blood samples were taken
at the commencement of the stabilization period and at the start (week
0), midpoint (week 3) and endpoint (week 6) of the test period and plasma
lipids analysed. The changes occurring on the linoleic acid-rich diet
and alpha-linolenic acid-rich diet were compared but no significant
differences in the changes in plasma total cholesterol, LDL-cholesterol,
HDL-cholesterol, the subfractions HDL2 and HDL3 or triacylglycerols
were found. These results indicate that dietary replacement of linoleic
acid with alpha-linolenic acid in the diet of healthy male subjects
offers similar cardioprotective benefits with respect to lipid metabolism.
Br J Nutr. 1998 Aug; 80(2): 163-7 Prevention of fatal cardiac arrhythmias
by polyunsaturated fatty acids.
In animal feeding studies, and probably in humans, n-3 polyunsaturated
fatty acids (PUFAs) prevent fatal ischemia-induced cardiac arrhythmias.
We showed that n-3 PUFAs also prevented such arrhythmias in surgically
prepared, conscious, exercising dogs. The mechanism of the antiarrhythmic
action of n-3 PUFAs has been studied in spontaneously contracting cultured
cardiac myocytes of neonatal rats. Adding arrhythmogenic toxins (eg,
ouabain, high Ca(2+), lysophosphatidylcholine, beta-adrenergic agonist,
acylcarnitine, and the Ca(2+) ionophore) to the myocyte perfusate caused
tachycardia, contracture, and fibrillation of the cultured myocytes.
Adding eicosapentaenoic acid (EPA: 5-15 micromol/L) to the superfusate
before adding the toxins prevented the expected tachyarrhythmias. If the
arrhythmias were first induced, adding the EPA to the superfusate terminated
the arrhythmias. This antiarrhythmic action occurred with dietary n-3
and n-6 PUFAs; saturated fatty acids and the monounsaturated oleic
acid induced no such action. Arachidonic acid (AA; 20:4n-6) is anomalous
because in one-third of the tests it provoked severe arrhythmias, which
were found to result from cyclooxygenase metabolites of AA. When cyclooxygenase
inhibitors were added with the AA, the antiarrhythmic effect was like
those of EPA and DHA. The action of the n-3 and n-6 PUFAs is to stabilize
electrically every myocyte in the heart by increasing the electrical
stimulus required to elicit an action potential by approximately 50% and
prolonging the relative refractory time by approximately 150%. These
electrophysiologic effects result from an action of the free PUFAs
to modulate sodium and calcium currents in the myocytes. The PUFAs
also modulate sodium and calcium channels and have anticonvulsant activity
in brain cells.
Am J Clin Nutr . 2000 Jan; 71(1 Suppl): 202S-7S
Prevention of sudden cardiac death by dietary pure omega-3
polyunsaturated fatty acids in dogs.
BACKGROUND: Rat diets high in fish oil have been shown to be protective
against ischemia-induced fatal ventricular arrhythmias. Increasing
evidence suggests that this may also apply to humans. To confirm the
evidence in animals, we tested a concentrate of the free fish-oil
fatty acids and found them to be antiarrhythmic. In this study, we
tested the pure free fatty acids of the 2 major dietary omega-3 polyunsaturated
fatty acids in fish oil: cis-5,8,11,14, 17-eicosapentaenoic acid (C20:5omega-3)
and cis-4,7,10,13,16, 19-docosahexaenoic acid (C22:6omega-3), and
the parent omega-3 fatty acid in some vegetable oils, cis-9,12,15-alpha-linolenic
acid (C18:3omega-3), administered intravenously on albumin or a phospholipid
emulsion. METHODS AND RESULTS: The tests were performed in a dog model
of cardiac sudden death. Dogs were prepared with a large anterior
wall myocardial infarction produced surgically and an inflatable cuff
placed around the left circumflex coronary artery. With the dogs running
on a treadmill 1 month after the surgery, occlusion of the left circumflex
artery regularly produced ventricular fibrillation in the control tests done
1 week before and after the test, with the omega-3 fatty acids administered
intravenously as their pure free fatty acid. With infusion of the eicosapentaenoic
acid, 5 of 7 dogs were protected from fatal ventricular arrhythmias (P<0.02).
With docosahexaenoic acid, 6 of 8 dogs were protected, and with alpha-linolenic
acid, 6 of 8 dogs were also protected (P<0.004 for each). The before and
after control studies performed on the same animal all resulted in fatal ventricular
arrhythmias, from which they were defibrillated. CONCLUSIONS: These results
indicate that purified omega-3 fatty acids can prevent ischemia-induced ventricular
fibrillation in this dog model of sudden cardiac death.
Circulation. 1999 May 11; 99(18): 2452-7
Arterial compliance
in obese subjects is improved with dietary plant n-3 fatty acid from
flaxseed oil despite increased LDL oxidizability.
The compliance or elasticity of the arterial system, an important
index of circulatory function, diminishes with increasing cardiovascular
risk. Conversely, systemic arterial compliance improves through eating
of fish and fish oil. We therefore tested the value of high intake
of alpha-linolenic acid, the plant precursor of fish fatty acids.
Fifteen obese people with markers for insulin resistance ate in turn
four diets of 4 weeks each; saturated/high fat (SHF), alpha-linolenic
acid/low fat (ALF), oleic/low fat (OLF), and SHF. Daily intake of
alpha-linolenic acid was 20 g from margarine products based on flax
oil. Systemic arterial compliance was calculated from aortic flow
velocity and aortic root driving pressure. Plasma lipids, glucose
tolerance, and in vitro LDL oxidizability were also measured. Systemic
arterial compliance during the first and last SHF periods was 0.42
+/- 0.12 (mean +/- SD) and 0.56 +/- 0.21 units based on milliliters
per millimeter of mercury. It rose significantly to 0.78 +/- 0.28
(P < .0001) with ALF; systemic arterial compliance with OLF was 0.62
+/- 0.19, lower than with ALF (P < .05). Mean arterial pressures and
results of oral glucose tolerance tests were similar during ALF, OLF, and
second SHF; total cholesterol levels were also not significantly different.
However, insulin sensitivity and HDL cholesterol diminished and LDL oxidizability
increased with ALF. The marked rise in arterial compliance at least with
alpha-linolenic acid reflected rapid functional improvement in the systemic
arterial circulation despite a rise in LDL oxidizability. Dietary n-3 fatty
acids in flax oil thus confer a novel approach to improving arterial function. Arterioscler Thromb Vasc Biol . 1997 Jun; 17(6): 1163-70
Alpha-linolenic acid and cardiovascular diseases.
The intake of saturated fat was postulated to be the main environmental factor
for coronary heart disease. It was also postulated that the noxious effects
of saturated fatty acids (FA) was primarily through the increase in serum cholesterol.
Nevertheless intervention trials either in coronary patients or even in primary
prevention did not observe significant reduction in cardiac mortality, especially
sudden death, when the diet was markedly enriched in linoleic acid (LA), the
most efficient FA to lower serum cholesterol. In intervention trials, It is
only when the diet was enriched in n-3 FA, especially alphalinolenic acid (
ALA ) that cardiac death was reduced. Studies in animals as well as in vitro
on myocytes in culture, have shown that ALA was preventing ventricular fibrillation,
the chief mechanism of cardiac death. Furthermore, studies in rats have observed
that among n-3 FA, ALA , the precursor of the n-3 family, may be more efficient
to prevent ventricular fibrillation than eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA). In addition it was demonstrated that ALA was the main FA lowering
platelet aggregation, an important step in thrombosis, i. e. non fatal myocardial
infarction and stroke. Thus, without side effects, a higher intake of ALA (2g
/ day) with a ratio of 5/1 for LA/ALA, could possibly constitute a nutritional
answer to the main cause of morbidity and mortality in industrialized countries.
J Nutr Health Aging . 2001; 5(3): 179-83
Perilla oil prevents the excessive growth of visceral adipose
tissue in rats by down-regulating adipocyte differentiation.
We examined the effect of dietary oils with different fatty acid compositions
on the growth of visceral adipose tissue in rats. Rats were fed for 4 mo starting
at weaning a basal diet containing (12 g/100 g diet) perilla oil rich in (n-3)
polyunsaturated fatty acids (PUFA), safflower oil rich in (n-6) PUFA, olive
oil rich in monounsaturated fatty acid, or beef tallow rich in saturated fatty
acids. The amount of food consumed and body weight gain did not differ among
the four dietary groups. The weight of the epididymal fat pad and the serum
triglyceride concentration in perilla oil-fed rats were significantly lower
(P < 0.05) than those of olive oil- and beef tallow-fed groups. The product
of [(volume of individual adipocytes) x (number of adipocytes in epididymal
fat pad)], which presumably represents total adipocyte volume in the fat pad,
was significantly lower (P < 0.05) in perilla oil-fed rats than in beef
tallow- and olive oil-fed groups. Expression of the late genes of adipocyte
differentiation, peroxisome proliferator-activated receptor alpha, adipocyte
P2 and adipsin, was significantly (P < 0. 05) down-regulated in epididymal
fat tissue of rats that had been fed perilla oil rather than beef tallow or
olive oil, whereas expression of the early gene, lipoprotein lipase, was not
significantly affected. Greater levels (P < 0.05) of (n-3) PUFA in the membrane
phospholipid fraction of the fat tissue were observed in perilla oil-fed rats
than in the other dietary groups. These results suggest that perilla oil or
(n-3) PUFA prevents excessive growth of adipose tissue in rats at least in
part by suppressing the late phase of adipocyte differentiation.
J Nutr . 1997 Sep; 127(9): 1752-7
N-3 and N-6 fatty acids in breast adipose tissue and relative
risk of breast cancer in a case-control study in Tours, France.
Experimental studies have indicated that n-3 fatty acids, including alpha-linolenic
acid (18:3 n-3) and long-chain n-3 polyunsaturated fatty acids inhibit mammary
tumor growth and metastasis. Earlier epidemiological studies have given inconclusive
results about a potential protective effect of dietary n-3 polyunsaturated
fatty acids on breast cancer risk, possibly because of methodological issues
inherent to nutritional epidemiology. To evaluate the hypothesis that n-3 fatty
acids protect against breast cancer, we examined the fatty acid composition
in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma
and from 88 patients with benign breast disease, in a case-control study in
Tours , central France . Fatty acid composition in breast adipose tissue was
used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies
of adipose tissue were obtained at the time of surgery. Individual fatty acids
were measured as a percentage of total fatty acids, using capillary gas chromatography.
Unconditional logistic regression modeling was used to obtain odds ratio estimates
while adjusting for age, height, menopausal status and body mass index. We
found inverse associations between breast cancer-risk and n-3 fatty acid levels
in breast adipose tissue. Women in the highest tertile of alpha-linolenic acid
(18:3 n-3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19-0.78)
compared to women in the lowest tertile (trend p = 0.01). In a similar way,
women in the highest tertile of docosahexaenoic acid (22:6 n-3) had an odds
ratio of 0.31 (95% CI = 0.13-0.75) compared to women in the lowest tertile
(trend p = 0.016). Women in the highest tertile of the long-chain n-3/total
n-6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17-0.66) compared
to women in the lowest tertile (trend p = 0.0002). In conclusion, our data
based on fatty acids levels in breast adipose tissue suggest a protective effect
of n-3 fatty acids on breast cancer risk and support the hypothesis that the
balance between n-3 and n-6 fatty acids plays a role in breast cancer.
Int J Cancer . 2002 Mar 1; 98(1): 78-83 |