Food and Food Supplements with Hypocholesterolemic Effects

Recent Patents on Food, Nutrition & Agriculture, 2009, 1, 15-24
15
Food and Food Supplements with Hypocholesterolemic Effects
Ruitang Deng*
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston,
Rhode Island, USA
Received: September 29, 2008; Accepted: October 16, 2008; Revised: October 18, 2008
Abstract: Hypercholesterolemia is a predominant risk factor for atherosclerosis and associated coronary and
cerebrovascular diseases. Control of cholesterol levels through therapeutic drugs, notably statins, have significantly
reduced the risk for developing atherosclerosis and associated cardiovascular diseases. However, adverse effects
associated with therapeutic drugs warrant to find other alternative approaches for managing hypercholesterolemia,
especially for those with borderline cholesterol levels. Food supplements have increasingly become attractive alternatives
to prevent or treat hypercholesterolemia and reduce the risk for cardiovascular diseases. This review summarized current
patents on food supplements with claims of hypocholesterolemic effects. They can be mainly divided into four categories
based on the active ingredients in the supplements: 1) plant sterols or stanols; 2) fiber or polysaccharides; 3)
microorganism-derived; and 4) soy protein and phytoestrogens. The efficacy, mechanisms of action and potential side
effects are reviewed for each of the four categories. The hypocholesterolemic effects of plant sterols, fiber, Monascus
products and soy protein preparations have been consistently demonstrated in clinical trails whereas the efficacy of some
probiotic bacteria and phytoestrogens-containing supplements remains to be established. Accumulative clinical data show
that plant sterols, fiber, soy protein and phytoestrogen are generally considered safe and cause no obvious side effects.
However, additional clinical studies are required to establish the safety profiles of certain probiotic bacteria as food
supplements.
Keywords: Cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), bile acids, plant sterols, plant
stanols, fiber, polysaccharides, soy protein, phytoestrogen, isoflavones, probiotic bacteria.
INTRODUCTION
Experimental and clinical studies have shown that the
amount of cholesterol transported in the VLDL, IDL and
Maintenance of cholesterol homeostasis is vital for
LDL classes of lipoproteins, known as pro-atherogenic
healthy status and achieved through a regulatory network
cholesterol, is a risk factor for the occurrence of cardio-
consisting of genes involved in cholesterol synthesis,
vascular disease [3, 9, 10]. In contrast, cholesterol trans-
absorption, metabolism and elimination. Imbalance of
ported in HDL particles, known as anti-atherogenic choles-
cholesterol level as a result of environmental and genetic
terol, has protective effect on cardiovascular disease [3, 9,
factors leads to hypercholesterolemia, a predominant risk
10].
factor for atherosclerosis and associated coronary and
cerebrovascular diseases [1-4]. Cardiovascular diseases

Control of cholesterol levels through therapeutic drugs
including coronary heart disease and stroke are the leading
have significantly reduced the risk for developing
cause of mortality, accounting for nearly 50% of all deaths in
atherosclerosis and associated cardiovascular diseases [11-
the Western developed world [5-7]. If the current trend
14]. Notably, statins, a class of cholesterol-lowering drugs
continues, the future will be even bleaker considering the
inhibiting cholesterol synthesis, have been most widely
fact that globalization and wide spread of Western diet to the
prescribed for treating hypercholesterolemia and reducing
developing world has encountered with explosive increase in
cardiovascular diseases [12-14]. However, adverse effects
the rates of obesity and hypercholesterolemia in those
associated with therapeutic drugs, such as myopathy, liver
regions. Therefore, hypercholesterolemia and its associated
damages and potential drug-drug interaction, have been
cardiovascular diseases represent one of the greatest
reported [15-19]. Therefore, development of additional
worldwide economic, social and medical challenges that we
therapies for controlling cholesterol levels is warranted,
are facing now [7, 8].
especially for those with better safety profile.
In blood plasma, cholesterol is transported by lipo-

Despite the wide use of therapeutic drugs for controlling
roteins, which can be mainly categorized into four classes,
blood cholesterol, the fact remains that it is estimated that
based on the size of cholesterol-lipoprotein complexes: the
greater than 50% of the population of the United States has
very-low-density lipoproteins (VLDL), the intermediate-
cholesterol levels at the borderline levels (ranging from 200
density lipoproteins (IDL), the low-density lipoproteins
to 239 mg/dL). Herbal remedies or food supplements have
(LDL), and the high-density lipoproteins (HDL) [1, 3].
increasingly become attractive alternatives to prevent or treat

hypercholesterolemia, especially for those with cholesterol at
the borderline levels. Excellent safety profile, cost-
*Address correspondence to this author at the Department of Biomedical
effectiveness and multiple beneficial effects on improving
and Pharmaceutical Sciences, College of Pharmacy, University of Rhode
Island, 41 Lower College Road, Kingston, RI 02881, USA;
well being all contribute to the emerging trend of
Tel: 401-874-4950; Fax: 401-874-5787; E-mail: DengR@mail.uri.edu

1876-1429/09 $100.00+.00
© 2009 Bentham Science Publishers Ltd.

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16 Recent Patents on Food, Nutrition & Agriculture, 2009, Vol. 1, No. 1
Ruitang Deng
increasingly usage of dietary or herbal supplement in United
their compositions, which consist of at least one of the plant
States and around the world.
sterols, stanols or their esters [25-35].
This review summarized current patents on food
Efficacy
studies: Clinical trials to evaluate the efficacy of
supplements with claims of hypocholesterolemic effects.
the compositions were carried out in majority of those
Those patents can be mainly divided into four categories
patents or patent applications. The results from those clinical
based on the active ingredients in the supplements: 1) plant
studies are summarized in Table 1. Consumption of plant
sterol or stanol; 2) fiber or polysaccharides; 3) microorga-
sterols-enriched food or food supplements for a period of 3.5
nism-derived; and 4) soy protein and phytoestrogens.
to 12 weeks result in significant decreases in both total
Distinct from early patents that mainly focus on single active
serum cholesterol and LDL-cholesterol with minimal effects
component in their claims, it becomes a current trend that
on HDL-cholesterol. The reductions range from 2.9% to
more than one active ingredient are claimed in the most of
12.0% for total serum cholesterol and 2.3% to 15.2% for
the recent patents or patent applications. Such combination
LDL-cholesterol, respectively Table 1. It should be noted
of active ingredients certainly further enhances the
that the efficacy obtained from most of the studies are not
therapeutic or preventive value of the food supplements [20],
solely due to the activity of plant sterols rather a combined
which provide patients with a relatively cheap, safe, and
effects of all the active ingredients in the claimed functional
effective way to manage their cholesterol levels and subse-
food or food supplements. The efficacy data reported in
quently reduce the cardiovascular risk.
those patents are consistent with the results obtained from
other clinical trials [36, 37]. Normen et al summarized 57
I. PLANT STEROLS OR STANOLS-ENRICHED
human trials using plant sterols and found that addition of
FOOD OR FOOD SUPPLEMENTS
plant sterol and stanol esters into foods such as margarine
Plant sterols are found in most plant foods and are
results in a mean reduction of LDL-cholesterol level of 9.9%
particularly abundant in vegetable oils and whole grains.
+ 3.9% [36]. Therefore, it can be concluded that
Plant sterols, also known as phytosterols, are structurally and
consumption of food supplements enriched with phytosterols
chemically similar to cholesterol and are unsaturated in their
have hypocholesterolemic effects.
sterol ring group. Plant stanols are saturated plant sterols and

Mechanisms of action: It has been well established that
typically less abundant in nature than plant sterols [21]. The
plant sterols exert their hypocholesterolemic effect by inhi-
most common phytosterols include -sitosterol, campesterol,
biting intestinal absorption of dietary as well as endogenous
and stigmasterol [22]. An ordinary diet normally contains
cholesterol [38, 39]. However, the molecular mechanisms for
plant sterols 100-300 mg/day. Most of the plant sterol in the
such inhibition are still not fully understood. It is generally
diet is -sitosterol, and approximately one-third is cam-
accepted that the presence of increased quantities of plant
pesterol. Small amounts of saturated 5 -sitostanols are also
sterols compete with cholesterol for micellar solubility,
present in food. Due to the proven effect on lowering
therefore lowering the amount of cholesterol available for
cholesterol level, the use of plant sterol-enriched products is
absorption by intestinal mucosal cells [40-42].
recommended by the International Atherosclerosis Society
[23] and the National Heart Foundation of Australia [24]. A
Potential side effects: Considering the fact that plant
number of recent patents or patent applications on food
sterols are present in most of dietary vegetable, fruits and
supplements claimed the hypocholesterolemic benefits of
nuts, and are poorly adsorbed by human body [43], plant
Table 1.
Efficacies of Phytosterol-Containing Food Supplements Reported in Recent Patents or Patent Applications
% Decrease in
% Decrease
Sample Size
Doses Duration
Statistic Analysis
Reference
Total Cholesterol
in LDL-Cholesterol
22
1.3g/day sterols
5 weeks
3.3
5.6
p<0.05*
[25]
100
3.31g/day, 65% esterified sterols
3.5 weeks
7.4
11.8
N/D**
[27]
100
3.3g/day, 85% esterified sterols
3.5 weeks
6.3
9.0
N/D
[27]
100 0.85g/day
3.5
weeks
3.8 6.1 N/D
[27]
100
0.85g/day, 85% esterified sterols
3.5 weeks
2.9
2.3
N/D
[27]
150
2.6g/day sterols
6 weeks
8.7
13.5
p<0.05
[29]
150
2.6g/day sterols
12 weeks
10.7
15.2
p<0.05
[29]
24
A diet with 12.5% -sitostanol 5
weeks
9.0
13.0
p<0.05
[29]
34 11g/day,
blend
Unknown
6.8
8.3 p<0.001
[30]
24
1.3g/day sterols
4 weeks
12.0
11.9
p<0.004
[31]
* The p value applied to the decrease in both total and LDL-cholesterol.
** N/D, statistic significance was not determined.

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Hypocholesterolemic Food Supplements
Recent Patents on Food, Nutrition & Agriculture, 2009, Vol. 1, No. 1 17
sterols are generally considered safe for consumption with
for 4 weeks led to reductions of 7.1% and 10.6% in mean
no obvious side effects [36, 37]. However, concerns have
total cholesterol and LDL-cholesterol, respectively. Such
been raised for high dose intake of plant sterols. First,
reductions were increased to 7.8% and 12.2% after 6 week
concomitant with cholesterol reduction, consumption of
consumption. On the other hand, HDL-cholesterol and
phytosterols decrease plasma concentrations of some fat
triglyceride levels remain unchanged [75]. Similar results
soluble vitamins, such as -carotene, -carotene, and vitamin
were reported from a randomized, double-blind, placebo-
E due to the inhibitory effect of phytosterols on their
controlled and parallel arm clinical study with 58 volunteers
absorption in the intestine [44-49]. Such reduced absorption
[76]. Intervention with daily intake of 15 g carob fiber for 6
becomes more pronounced when higher levels of plant sterol
weeks reduced LDL cholesterol by 10.5 % [76]. In another
intake occur. On the other hand, studies also show that
clinical study with 16 subjects, consumption of fiber-
consumption of phytosterols does not significantly affect
enriched food supplement (46.2% fiber: 16.5% soluble and
serum vitamin A (retinol), vitamins D and K [47, 49-52].
29.7% insoluble) for 21 days decreased total cholesterol
The second concern is raised regarding the potential
levels by 5 to 7.5% in 7 subjects and 8 to 11% in 6
atherogenicity of elevated serum phytosterols in certain
participants with no significant change in 3 subjects [71]. In
individuals. Supporting such concern is the presence of
a long term 51 week study with 59 subjects with moderate
coronary atherosclerosis in sitosterolemic patients, charac-
hypercholesterolemia, daily intake of 20 g of a mixture of
terized by severely elevated serum phytosterols without
dietary fibers (guar gum, pectin, soy, pea, corn bran) as food
increase in cholesterol levels [53-55]. In addition, other
supplement reduced total cholesterol by 5% and LDL-
epidemiological studies report a potential linkage between
cholesterol by 9% [77]. The reductions were apparent after 3
phytosterols and atherosclerosis [56-59]. However, such
weeks of treatment. There were no significant effects on the
possible association has not been confirmed in studies with
levels of either triglycerides or HDL-cholesterol [77]. It has
animal model and human subjects [60-62]. Mice with
been reported that oat bran reduces the cholesterol level
inactivation of ATP-binding cassette (ABC) transporters G5
primarily because of its -glucan content. Daily uptake of
and G8 (ABCG5/8) exhibit over 20-fold increase in serum
7.2 g of oat gum for 4 weeks with 20 hypercholesterolemic
phytosterols but no significant differences in aortic lesions
patients decreased total cholesterol levels by 9% with no
are found when compared with wt control mice [60]. Also,
significant changes in HDL-cholesterol and triglyceride
studies with human subjects found no association between
levels [78]. Taken together, the hypocholesterolemic effects
phytosterols and atherosclerosis or cardiovascular diseases
of various fibers have been demonstrated in both preclinical
[60-62]. Taken together, it appears that the role plant sterols
and clinical studies. The magnitudes of reduction depend on
plays in the development of atherosclerosis is not conclusive
the type of fiber, dose, intervention duration and the
and additional studies are warranted.
hypercholesterolemic status of the subjects.
II. FIBER OR POLYSACCHARIDE-ENRICHED
Mechanisms of action: Currently, the mechanisms for
FOOD SUPPLEMENTS
cholesterol-lowering effect of water soluble fiber are not
fully understood. One favorite hypothesis is that water-

It has been well established that dietary fiber has many
soluble fiber binds to bile acids and decrease bile acid
health benefits including decrease in serum LDL-cholesterol,
reabsorption in the intestine [79-82]. Conversion of choles-
improving triglycerides, and weight management [63-69].
terol into bile acids is one of major pathways for removing
Compared with low-fiber diet, a high-fiber diet is associated
cholesterol from the body and is negatively regulated by bile
with a lower risk of atherosclerosis [66-69]. Whole grain
acids through repressing cholesterol 7 -hydroxylase
food made of wheat, oat, barley and rye or food made of
(CYP7A1), the rate-limiting enzyme for bile acid synthesis
bran, such as oat bran, rice bran, soy bran and wheat bran
[83-87]. Decreased reabsorption of bile acids thus favors
contain high fiber. Fiber can be categorized into water
cholesterol conversion into bile acids. On the other hand, as
soluble and insoluble. The four major water soluble fibers
biological detergents, bile acids are required for cholesterol
are -glucan, psyllium, pectin and guar gum and have been
solubilization and absorption in the intestine. Binding of bile
used widely as food additive to increase fiber content. The
acids to fiber decreases free bile acids for solublizing
most common insoluble fiber includes cellulose and lignin.
cholesterol, thus decreasing cholesterol absorption. The
Several recent patents have claims for using fiber or
mechanism for insoluble fiber to exert hypocholesterolemic
polysaccharides to manage hypercholesterolemia. In addition
effect is largely unknown. A recent study shows that intake
to -glucan, psyllium and fiber from oats, peas, beans, soy
of insoluble fiber derived from cell wall significantly
and grain bran [25, 28, 30, 70-74], polysaccharides from
increases fecal excretion of both bile acids and neutral sterols
bacterium such as lactobacillus strain [70], and insoluble
[88]. Such increased fecal excretion of bile acids may lead to
fiber from carob pulp were also claimed [73, 74].
hypocholesterolemic effect through similar mechanism as

Preclinical and clinical studies: In a mouse study using
water soluble fiber.
reuteran, a branched CC-1, 4/1, 6-glucan produced by some

Potential side effects: Results from clinical studies show
Lactobacillus reuteri strains, it was showed that feeding a
that fiber supplementations are generally well tolerated. No
“Western diet” with 10% reuteran for 15 days resulted in a
obvious side effects have been reported from consuming
decrease in total cholesterol levels by 36.8% [70]. The lipid-
fiber-enriched diet or fiber supplements. In one study using
lowering effect of a carob pulp preparation rich in insoluble
insoluble carob fiber, it was reported that 3 volunteers (6%)
dietary fiber was evaluated in 50 patients with moderate
felt a sensation of fullness, which led to 2 volunteers dropout
hypercholesterolemia (total cholesterol 232-302 mg/dL)
the study [71]. The excellent safety profile of fiber may be
[75]. Consumption of 15 g carob fiber per day as supplement
related to the fact that fiber, particular insoluble fiber, is

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18 Recent Patents on Food, Nutrition & Agriculture, 2009, Vol. 1, No. 1
Ruitang Deng
poorly adsorbed in the intestine, avoiding systemic entering
the results from the preclinical studies, significant reduction
into the body [89].
in total and LDL-cholesterol levels were achieved following
intake of various Monascus preparations in hypercholes-
III. MICROORGANISM-DERIVED FOOD SUPPLE-
terolemic patients or healthy volunteers [92, 109-113]. In a
MENTS
small pilot study, 4 out of 6 volunteers consuming 65 mg

Probiotic agents are referred to live organisms, such as
Monascus composition daily for 2 weeks decreased total
bacteria, which confer not only traditional nutrition values
cholesterol by 19.8% and LDL-cholesterol by 22.6% [92]. In
but also health benefits when they are consumed. Probiotic
a clinical study with 131 moderately hypercholesterolemic
products have a long history of being used as food
patients, the hypocholesterolemic effect of Monascus
supplements, especially in Asia and Europe, and are now
purpureus was evaluated in comparison with cholesterol-
becoming a new popular category of food supplements in the
lowering drug pravastatin [109]. One hundred and eleven
United States. Two probiotic agents, including Bacillus
subjects received Monascus purpureus extract whereas 20
coagulans and Rhodospirillum rubrum, and fungi Monascus,
participants took pravastatin. At the end of study, total
are claimed in the recent patent applications for managing
cholesterol was significantly reduced by about 20% in both
hypercholesterolemia [90-92]. Bacillus coagulans is a non-
groups, suggesting similar efficacy between Monascus
pathogenic lactic acid-producing bacterium and has been
purpureus extract and pravastatin [109]. In a clinical study
used for production of lactic acid [93], fermented food [94]
with 72 patients to assess the efficacy and safety of
and animal feeds additives [95, 96]. Rhodospirillum rubrum
Monascus purpureus Went rice in the management of
is a member of Rhodospirillum genus, characterized by
nephrotic dyslipidemia, oral administration of Monascus
being phototrophic using light as an energy source. The
purpureus Went rice in a dose of 600 mg twice per day for
bacterium is found in natural water and mud, and is used in
one month and then once daily for 11 months significantly
sewage purification, biomass production of animal foodstuff
reduced cholesterol levels in 6 and 12 months [110]. In
and plant fertilizer [97]. Fungi Monascus are used for
another clinical trail with 79 patients, consumption of
production of fermented red rice, red rice wine and other
Monascus purpureus Went rice at a dose of 600 mg daily for
food products [98, 99]. Due to their ability to produce
8 weeks reduced LDL-cholesterol by 27.7% and total choles-
different color pigments, Monascus strains are also widely
terol by 21.5% [111]. Similar efficacy was also obtained in a
used by food and cosmetic industries for coloring agents.
study (15 hypercholesterolemic patients) with Monascus
garlic fermented extract. Intake of 450mg of extract daily for
Preclinical and Clinical studies: In a study with 17
4 weeks significantly reduced total and LDL-cholesterol
hyperlipidemic patients, intake of 360 million spores of
levels [112]. Liu et al. summarized 93 randomized clinical
Bacillus daily for 3 months significantly reduced total
trials with a total of 9625 subjects and found that
cholesterol by 31.5% and LDL-cholesterol by 35.2% with a
consumption of Chinese red yeast rice extract, a traditional
marginal increase in HDL-cholesterol and no change in
dietary seasoning of Monascus purpureus, resulted in
triglyceride level [100]. In a controlled study with 20
significant reduction in both total and LDL-cholesterol levels
patients, consumption of two tablets (0.5g per capsule of
[113]. In addition, the hypocholesterolemic activities of the
Bacillus coagulans dry powder) daily for 60 days decreased
extract appeared to be comparable to the therapeutic statin
LDL cholesterol by 31-43% and serum triglyceride levels by
drugs [113]. Taken together, the hypocholesterolemic effect
11-16% while increased HDL cholesterol level by 7-15%. In
of Monascus preparations have been consistently demons-
addition, the intervention significantly reduced the carotid
trated in preclinical and clinical studies.
artery blockage in 3 of the patients from greater than 85% to
about 40% [90].
Mechanisms of action: It is currently unknown how
Bacillus and Rhodospirillum bacteria exert their observed

In a preclinical study with male Wistar rats, animals
hypocholesterolemic effect. As probiotic bacteria, it is
receiving a chow diet containing additional 10% (v/v)
generally believed that those bacteria confer a healthy
freeze-dried Rhodospirillum rubrum for 8 weeks exhibited a
benefit by colonizing in the gut and inhibiting the growth of
significant reduction in serum total cholesterol by 25%
other pathogenic organisms in the same environment [114-
compared with the animals receiving chow diet. Further
117]. Another hypothesis is that probiotic bacteria produce
analysis of the cholesterol fractions revealed that the
specific enzymes or metabolites beneficial for improving the
decrease in total cholesterol level was due to a decrease in
pathological conditions, such as hypercholesterolemia.
the plasma LDL fraction, while the HDL fraction remained
However, no direct evidence has been demonstrated. It has
unchanged in the Rhodospirillum rubrum-fed animals [91].
been well established that fungi Monascus naturally produce
Similar results were achieved in a short-term study with
bioactive compounds monacolins, which inhibit the 3-
C57Black/6 mice. Feeding mice with 10% Rhodospirillum
hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-
rubrum-containing diet for a week reduced total serum
tase. Among those monacolins, monacolin K is identical to
cholesterol level by 20% in comparison with mice receiving
the potent cholesterol-lowering drug lovastatin [118, 119].
regular chow diet [91].
Although the yields of monacolins produced vary by

Extensive preclinical and clinical trials have been carried
different Monascus strains under various incubation condi-
out to evaluate the cholesterol-lowering effect of Monascus-
tions, the hypocholesterolemic effects of those Monascus
derived preparations. In preclinical studies, the hypo-
preparations are believed to be due to the presence of
cholesterolemic activity of Monascus preparations was
monacolins. However, such notion was challenged by the
demonstrated in rat [101, 102], hamster [103-104], rabbit
finding that potent hypocholesterolemic activity were
[105, 106], quail [107], and chicken [108]. Consistent with
detected in Monascus preparations lacking monacolins [92],

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Hypocholesterolemic Food Supplements
Recent Patents on Food, Nutrition & Agriculture, 2009, Vol. 1, No. 1 19
indicating the presence of other bioactive compounds
variations exist in sample size, patient hypercholesterolemic
responsible for the observed activity.
status, preparation process, dose and intervention duration, it
appears that soy protein consumption decreases total choles-
Potential side effects: As a widely used probiotic
terol levels most significantly in subpopulation with severe
bacterium, Bacillus is generally considered safe. Such view
hypercholesterolemia with moderate effect in moderately
is supported by clinical and epidemiological studies [120].
hypercholesterolemic patients and marginal or minimal
Currently, no clinical data are available for assessing the
effect in low or non-hypercholesterolemic subjects [131-
safety of Rhodospirillum preparations as food supplement. In
133]. Consistent with such trend is the results from a small
a preclinical study with rats, feeding of a 10% freeze-dried
clinical study with 15 patients in a recent patent application
Rhodospirillum-containing diet for 8 weeks resulted in no
[125]. Daily consumption of 5 g soy protein preparation for
significant changes in various clinical and toxicological
2 months reduced total serum cholesterol levels by16.4%,
parameters, including plasma glucose, uric acid, urea,
7.8% and 2.4% in subjects with high, medium and low
creatinine, glutamyl oxaloacetic transaminase, glutamyl
pretreatment cholesterol levels, respectively [124].
pyruvic transaminase, haematocrit, and haemoglobin, and
urinary glucose and protein [91]. Such safety profile is

Efficacy regarding phytoestrogens, such as isoflavones,
consistent with the current practice that Rhodospirillum
in reducing cholesterol levels is still questionable. Several
strains are used as animal feed additives [97]. Monascus has
clinical studies showed that isoflavones or isoflavones-
a long history being used as food supplements in Asia and is
enriched preparations had significant hypocholesterolemic
considered safe [98, 99]. However, concern has been raised
activity reducing total cholesterol levels from 6.5% to 10.2%
regarding some Monascus strains producing a second
[134-137]. However, such hypocholesterolemic claim has
metabolite mycotoxin citrinin under certain conditions.
been challenged by the results from other clinical trials [138-
Citrinin is found hepatotoxic and nephratoxic, adversely
144]. Those studies found that consumption of isoflavones at
affecting the function of both liver and kidney [98].
various doses failed to significantly reduce cholesterol levels
Therefore, minizing citrinin content is a priority to improve
or reduction of cholesterol levels by soy protein preparations
the safety of Monascus-containing food supplement. In
was independent of isoflavones. One possible explanation
addition, the active ingredients monakolins in Monascus
for such discrepancy may be that the expression of dose in
preparations may have similar side effects exhibited by
total isoflavone is not the adequate measurement as
therapeutic statin drugs. Finally, it should be emphasized that
variations in types (such as genistein vs daidzein) and forms
as living organisms, probiotics carry theoretical safety risks
(such as aglycone, glycoside, vs malonyl glycoside) of
as food supplements. Such risks include acquiring virulence
isoflavones may have significant impact on cholesterol-
factors or antibiotic resistance from environments or
lowering activity. Alternatively, the results suggest that
pathogenic organisms [121]. Although such incidence has
isoflavones are not the active ingredients in soy protein
not been reported, surveillance measurements should be
preparations responsible for the hypocholesterolemic acti-
implemented to ensure the safety of those products.
vity. In a small clinical trial with 7 healthy volunteers, daily
consumption of 100-150 g navy bean (containing 60-100 mg
IV. SOY PROTEIN AND PHYTOESTROGEN AS
isoflavones) for 3 weeks had no effect on total cholesterol
FOOD OR FOOD SUPPLEMENTS
levels. However, daily intake of 5 g red clover extracts

It has been a long history that as a high quality protein,
(containing 100 mg isoflavones) significantly reduced total
soy protein is widely used as an excellent alternative source
serum cholesterol levels by an average of 7.3% [124].
for animal protein, especially in Asian countries. A variety
Whether other components in the red clover extracts other
of soy protein products are currently available on the food
than isoflavones produced such benefit remains to be
market, such as tofu, soy butter, soy nuts, soy milk and some
determined. Taken together, most of human clinical trials
soy burgers. Consumption of soy protein products in the
support the notion that soy protein preparations have
United States has grown significantly since a healthy benefit
hypocholesterolemic effects. However, the efficacy of
claim of soy protein was issued by FDA in 1999 [122]. Soy
phytoestrogens, such as isoflavones, has not been fully
protein preparations are enriched with isoflavones, known as
established.
phytoestrogens. The major isoflavones in soy protein

Mechanisms of action: The molecular mechanisms for
preparations include genistein, daidzein, glycitein, their
soy protein preparations to exert cholesterol-lowering effect
naturally occurring glycosides (genistin, daidzin and
are still unknown. Although it was once proposed that
glycitin), and malonyl glycosides. Their abundance in soy
isoflavones enriched in soy protein preparations were the
protein preparations varies widely and depends on the
active ingredients, more and more evidence suggest that
processing techniques used during production [123]. In
components other than isoflavones might be responsible for
addition to soy protein, other plants such as red clover also
the activity. Isoflavones have a spatial structure similar to
contain high amount of phytoestrogens. Several current
mammalian estrogens, such as 17 -estrodiol (E2) with weak
patent applications have claims using soy protein or
agonistic activity to estrogen receptors (ERs). Compared
phytoestrogens as at least one of the ingredients in their
with E2, isoflavones have about one hundredth to one
compositions to manage hypercholesterolemia [25, 28, 33
thousandth ER agonistic activity exhibited by E2. Studies
71, 124, 125].
with various approaches have shown that isoflavones bind to
Clinical
studies: Extensive clinical trials have been
the ligand binding domain of ER in a very similar fashion as
carried out to evaluate the hypocholesterolemic benefit of
E2 except for the interaction with helix 12 of the receptors
soy protein preparations and the data from most of those
[145, 146]. Considering the fact that isoflavones exhibit over
clinical studies have been reviewed [126-130]. Although
20 times higher binding affinity for ER than for ER , it was

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20 Recent Patents on Food, Nutrition & Agriculture, 2009, Vol. 1, No. 1
Ruitang Deng
proposed that isoflavones should not be considered as typical
related to a high intake of soy products. In summary, soy
“estrogens” rather as natural selective estrogen receptor
protein preparations and phytoestrogens are generally
modulators (SERM) [147]. As SERMs, isoflavones can exert
considered safe and well tolerated with no increase in risk
partial agonist or antagonist actions on ER in a tissue-,
for cancers. However, additional studies with high doses and
pathway- or isoform-specific manner. Estrogen and certain
long-term are required to ascertain their safety.
SERMs have been shown to have hypolipidemic properties
CURRENT & FUTURE DEVELOPMENTS
[148, 149] whereas other SERMs have been reported to
inhibit estrogen’s cardiovascular protective function [150].

Food supplements have increasingly become attractive
Thus, it remains to be determined: 1) whether isoflavones are
alternatives to prevent or treat hypercholesterolemia and
the active ingredients for soy protein’s hypocholesterolemic
reduce the risk for cardiovascular diseases. The hypocho-
effect; and 2) whether isoflavones act as agonists or
lesterolemic effects of plant sterols, fiber, Monascus
antagonists of ER to exert their possible hypocholestero-
products and soy protein preparations have been consistently
lemic activity.
demonstrated in clinical trails whereas the efficacy of certain
Potential side effects: As estrogenic compounds,
probiotic bacteria, such as Bacillus and Rhodospirillum, and
concerns have been raised for phytoestrogens to be used as
phytoestrogens-containing supplements remains to be fully
food supplements. One critical question is whether
established. The active ingredients in soy protein prepa-
phytoestrogens increase the risk of cancers, especially breast
rations responsible for the hypocholesterolemic effects
cancer and prostate cancer. Several clinical studies have been
remains to be elucidated as more and more evidence
conducted to evaluate such possible side effect [151-155].
indicates that isoflavones, once believed to be the active
The results from those studies indicate that phytoestrogens
ingredients, might not be the mediators of the hypocho-
are well tolerated and do not increase the risk for breast and
lesterolemic activity of soy protein products. Currently, our
prostate cancer. In a study with 30 healthy postmenopausal
understanding on the molecular mechanisms for most of
women, daily administration of 900 mg soy isoflavones for
those active ingredients is incomplete or still lacking,
84 days had no detectable effects on DNA damage,
especially for probiotic bacteria and soy protein preparations.
apoptosis, and changes indicative of estrogenic stimulation.
Although it is becoming a trend to combine various active
It was concluded that unconjugated soy isoflavones appeared
ingredients to enhance the efficacy of food supplements in
to be safe and well tolerated in healthy postmenopausal
lowering cholesterol, most of such combinations are based
women [151]. In a recently reported study, the associations
on a trial-error approach. Understanding the underlying
between dietary phytoestrogen (isoflavonoids, lignans, and
mechanisms will provide the molecular basis for rational
coumestrol) intake and risk of breast cancer were evaluated.
combination of active ingredients to achieve maximal
The results revealed that intakes of lignan, isoflavonoid, or
beneficial effects and minimize potential adverse reaction.
coumestrol were not associated with breast cancer risk

Accumulative data from preclinical and clinical studies
overall or before or after 50 years of age [152]. In a
show that plant sterols, fiber, soy protein and phytoestrogens
randomized, double-blind, placebo-controlled pilot trial with
are generally considered safe and cause no obvious side
401 healthy women aged 35-70 years with a family history
effects. However, no clinical data are currently available for
of breast cancer, the safety and tolerability of a standardized
evaluating the safety of probiotic Rhodospirillum prepa-
40 mg red clover isoflavone dietary supplement were
rations. Future clinical studies are required to establish the
evaluated for three years [153]. No significant differences in
safety profiles of probiotic Rhodospirillum as food supple-
breast density, endometrial thickness, serum cholesterol,
ment. Finally, new approaches, such as genetic modification
follicle stimulating hormone levels and bone mineral density
of Monascus strains and alteration of production process, to
were detected between those taking red clover isoflavones
minimize or totally eliminate the production of mycotoxin
and placebo. The results support the growing body of
citrinin should be taken to ensure the safety of Monascus
evidence that treatment with red clover isoflavones is safe
products as food supplements.
and well tolerated in healthy women [154]. Two recent
clinical studies investigated the possible side effects of
ACKNOWLEDGMENTS
isoflavones on men with or without prostate cancer [155,

The work done in author’s lab was partially supported by
156]. Fifty three prostate cancer patients received either
funding from New Investigator Program for Pharmacy
purified isoflavones (80 mg daily) or placebo for 12 weeks.
Faculty, American Association of Colleges of Pharmacy; the
At the end of the study, although significant increases in
Medical Research Grant from the Rhode Island Foundation;
plasma isoflavones were detected, no clinical toxicity was
the Rhode Island-IDeA Network of Biomedical Research
detected [154]. The other study assessed the effect of an
Excellence grant P20 RR016457 from National Center for
isoflavonoid extract from red clover on prostate, liver
Research Resources/NIH; and the Faculty Research
function, quality of life, and sexual function in men. Twenty
Development Grant, University of Rhode Island.
men (mean age 65 years) were treated with a daily dose of
60 mg isoflavone extract for 1 year. It was concluded that
CONFLICT OF INTEREST
daily oral administration of 60 mg of the isoflavone extract

The authors has no conflict of interest.
was well tolerated and caused no side effects [155]. In
contrast to the favorable findings from those clinical studies,
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