Research On Resveratrol
Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of
red grapes, is a component of Ko-jo-kon, an oriental medicine used to treat diseases of
the blood vessels, heart, and liver. It came to scientific attention only a few years ago,
however, as a possible explanation for the "French Paradox" -- the low incidence of heart
disease among the French people, who eat a relatively high-fat diet. Today, it is touted
by manufacturers and being examined by scientific researchers as an antioxidant, an
anti-cancer agent, and a phytoestrogen. It is also being advertised on the Internet as
"The French Paradox in a bottle." This article reviews the recent research on resveratrol's physiologic activity.
Resveratrol is the parent compound of a family of molecules,
including glucosides and polymers, existing in cis and trans
configurations in a narrow range of spermatophytes of which vines,
peanuts and pines are the prime representatives. Its synthesis from
p-coumaroyl CoA and malonyl CoA is induced by stress, injury, infection
or UV-irradiation, and it is classified as a phytoalexin anti-fungicide
conferring disease resistance in the plant kingdom. In vitro, ex vivo
and animal experiments have shown that it possesses many biological
attributes that favour protection against atherosclerosis, including
antioxidant activity, modulation of hepatic apolipoprotein and lipid
synthesis, inhibition of platelet aggregation as well as the production
of pro-atherogenic eicosanoids by human platelets and neutrophils. Red
wine represents its main source in the human diet, and it has been
proposed as a major constituent of the polyphenol fraction to which the
health benefits of red wine consumption have been attributed. The past
several years have witnessed intense research devoted to its
measurement in wine and the factors likely to promote its enrichment in
this beverage. Up to the present, conclusive evidence for its
absorption by human subjects in biologically significant amounts is
lacking, and it is questionable (but not yet excluded) that its
powerful and beneficial in vitro activities are reproduced as a
consequence of sustained moderate red wine consumption.
Resveratrol, a phytoalexin found in grapes and other food products, was purified and
shown to have cancer chemopreventive activity in assays representing three major stages of
carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to
induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated
anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions
(antipromotion activity); and it induced human promyelocytic leukemia cell differentiation
(antiprogression activity). In addition, it inhibited the development of preneoplastic
lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis
in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of
the human diet, merits investigation as a potential cancer chemopreventive agent in
humans.
While present in other plants, such as eucalyptus, spruce, and lily,
and in other foods such as mulberries and peanuts, resveratrol's most
abundant natural sources are Vitis vinifera, labrusca, and muscadine
grapes, which are used to make wines. It occurs in the vines, roots,
seeds, and stalks, but its highest concentration is in the skin, which
contains 50-100 micrograms (µg) per gram. Resveratrol is a phytoalexin,
a class of antibiotic compounds produced as a part of a plant's defense
system against disease. For example, in response to an invading fungus,
resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA. Since
fungal infections are more common in cooler climates, grapes grown in
cooler climates have a higher concentration.
The resveratrol content of wine is related to the length of time the
grape skins are present during the fermentation process. Thus the
concentration is significantly higher in red wine than in white wine,
because the skins are removed earlier during white-wine production,
lessening the amount that is extracted. Grape juice, which is not a
fermented beverage, is not a significant source of resveratrol. A fluid
ounce of red wine averages 160 µg of resveratrol, compared to peanuts,
which average 73 µg per ounce. Since wine is the most notable dietary
source, it is the object of much speculation and research.
Resveratrol is a compound produced by many plant species and is thought to be helpful
in reducing serum lipids and may have favorable cardiovascular implications. It is
produced by Vitis vinifera and labrusca grapes and is found in grape products including
red and white wines. There is a lack of information about resveratrol in muscadine (V.
rotundifolia), so two studies were made to check bronze- and dark-skinned muscadines (and
products made from them) for resveratrol. The first study established that resveratrol is
a natural constituent of muscadine berries, berries without seed and seeds alone. The
second study measured resveratrol in such muscadine products as wine, unfiltered juice,
pomace and in purees made from pomace. Significant amounts of resveratrol were found in
pomace. Muscadines wines compared favorably in resveratrol concentration with wines
reported in the literature. The consumption of muscadines and muscadine products,
especially those made from pomace purees, could help incorporate a sign
ificant quantity of resveratrol into the average diet.
Many studies suggest that consuming alcohol (especially red wine) may reduce the
incidence of coronary heart disease (CHD). Several studies have demonstrated that
resveratrol is an effective antioxidant. It inhibits lipid peroxidation of low-density
lipoprotein (LDL), prevents the cytotoxicity of oxidized LDL, and protects cells against
lipid peroxidation. It is thought that because it contains highly hydrophilic and
lipophilic properties, it can provide more effective protection than other well-known
antioxidants, such as vitamins C and E. On the other hand, it is less effective than the
antioxidants quercetin and epicatechin found in red wine. Reduced platelet aggregation has
also been demonstrated in studies on resveratrol, further contributing to its prevention
of atherosclerosis. To date, most of the research on resveratrol's antioxidant and
anti-platelet properties has been done in vitro (in an artificial environment using
test-tube or tissue-culture preparations). Further studies in animals and humans
are necessary to determine whether resveratrol supplementation makes sense.
Resveratrol is being studied to see how it affects the initiation,
promotion, and progression of cancer. With regard to tumor initiation,
it has been shown to act as an antioxidant by inhibiting free radical
formation, and as an anti-mutagen in rat models. Resveratrol appears to
decrease tumor promotion activity by inhibiting cyclooxygenase-1
(COX-1), an enzyme that converts arachidonic acid to pro-inflammatory
substances that stimulate tumor-cell growth. Studies related to
progression have found that resveratrol induced human promyelocytic
leukemia cell differentiation and inhibited ribonucleotide reductase,
an enzyme needed for DNA synthesis in proliferating cells. One
appealing characteristic of resveratrol's anti-cancer potential is its
minimal toxicity to blood-forming cells. More studies using both
cellular and animal models are needed before any such data would be
applicable to human use.
The similarity in structure between resveratrol and diethylstilbestrol (a synthetic
estrogen) has prompted investigations into resveratrol's potential as a phytoestrogen (a
plant compound that produces estrogen-like effects). However, these properties also
stimulate the growth of human breast cancer cells. This finding seems contrary to its
other anticancer activities, and is a cause for concern.
A group of Functional Foods for Health (FFH) Program scientists led by Dr. John Pezzuto
in the College of Pharmacy at the UIC campus have recently shown that a substance in
grapes may prevent cancer.
In the study, Pezzuto and colleagues were able to show that resveratrol was effective
during all three phases of the cancer process: initiation, promotion and progression.
Resveratrol was found to have antioxidant and antimutagenic activity and also increased
levels of the phase II drug-metabolizing enzyme quinone reductase, an enzyme capable of
metabolically detoxifying carcinogens, thereby ridding them from the body. All three of
these physiological effects are indicative of resveratrol preventing cancer
initiation--the initial, irreversible stage of the cancer process. Resveratrol also demonstrated antiinflammatory effects and
inhibited the activity of the cyclooxygenase and hydroperoxidase enzymes (suggestive of
antipromotion activity) in addition to causing the differentiation of human promyelocytic
leukemia cells, indicating that this compound may also depress the progression phase of
cancer. Finally, resveratrol inhibited the development of preneoplastic lesions in mouse
mammary glands treated with a carcinogen in culture and inhibited tumor formation in mice.
No toxic effects were observed.
The UIC researchers originally isolated resveratrol from a crude extract of the roots
of a tree collected in Peru under a grant from the National Cancer Institute which
involves screening for cancer-inhibiting compounds from plants. According to Pezzuto, "Of
all the plants we've tested for cancer chemopreventive activity and all the compounds
we've seen, this one has the greatest promise."
See also Flavonoids.html">Flavonoids and Quercetin
Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of
red grapes, is a component of Ko-jo-kon, an oriental medicine used to treat diseases of
the blood vessels, heart, and liver. It came to scientific attention only a few years ago,
however, as a possible explanation for the "French Paradox" -- the low incidence of heart
disease among the French people, who eat a relatively high-fat diet. Today, it is touted
by manufacturers and being examined by scientific researchers as an antioxidant, an
anti-cancer agent, and a phytoestrogen. It is also being advertised on the Internet as
"The French Paradox in a bottle." This article reviews the recent research on resveratrol's physiologic activity.
Resveratrol is the parent compound of a family of molecules,
including glucosides and polymers, existing in cis and trans
configurations in a narrow range of spermatophytes of which vines,
peanuts and pines are the prime representatives. Its synthesis from
p-coumaroyl CoA and malonyl CoA is induced by stress, injury, infection
or UV-irradiation, and it is classified as a phytoalexin anti-fungicide
conferring disease resistance in the plant kingdom. In vitro, ex vivo
and animal experiments have shown that it possesses many biological
attributes that favour protection against atherosclerosis, including
antioxidant activity, modulation of hepatic apolipoprotein and lipid
synthesis, inhibition of platelet aggregation as well as the production
of pro-atherogenic eicosanoids by human platelets and neutrophils. Red
wine represents its main source in the human diet, and it has been
proposed as a major constituent of the polyphenol fraction to which the
health benefits of red wine consumption have been attributed. The past
several years have witnessed intense research devoted to its
measurement in wine and the factors likely to promote its enrichment in
this beverage. Up to the present, conclusive evidence for its
absorption by human subjects in biologically significant amounts is
lacking, and it is questionable (but not yet excluded) that its
powerful and beneficial in vitro activities are reproduced as a
consequence of sustained moderate red wine consumption.
Resveratrol, a phytoalexin found in grapes and other food products, was purified and
shown to have cancer chemopreventive activity in assays representing three major stages of
carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to
induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated
anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions
(antipromotion activity); and it induced human promyelocytic leukemia cell differentiation
(antiprogression activity). In addition, it inhibited the development of preneoplastic
lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis
in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of
the human diet, merits investigation as a potential cancer chemopreventive agent in
humans.
While present in other plants, such as eucalyptus, spruce, and lily,
and in other foods such as mulberries and peanuts, resveratrol's most
abundant natural sources are Vitis vinifera, labrusca, and muscadine
grapes, which are used to make wines. It occurs in the vines, roots,
seeds, and stalks, but its highest concentration is in the skin, which
contains 50-100 micrograms (µg) per gram. Resveratrol is a phytoalexin,
a class of antibiotic compounds produced as a part of a plant's defense
system against disease. For example, in response to an invading fungus,
resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA. Since
fungal infections are more common in cooler climates, grapes grown in
cooler climates have a higher concentration.
The resveratrol content of wine is related to the length of time the
grape skins are present during the fermentation process. Thus the
concentration is significantly higher in red wine than in white wine,
because the skins are removed earlier during white-wine production,
lessening the amount that is extracted. Grape juice, which is not a
fermented beverage, is not a significant source of resveratrol. A fluid
ounce of red wine averages 160 µg of resveratrol, compared to peanuts,
which average 73 µg per ounce. Since wine is the most notable dietary
source, it is the object of much speculation and research.
Resveratrol is a compound produced by many plant species and is thought to be helpful
in reducing serum lipids and may have favorable cardiovascular implications. It is
produced by Vitis vinifera and labrusca grapes and is found in grape products including
red and white wines. There is a lack of information about resveratrol in muscadine (V.
rotundifolia), so two studies were made to check bronze- and dark-skinned muscadines (and
products made from them) for resveratrol. The first study established that resveratrol is
a natural constituent of muscadine berries, berries without seed and seeds alone. The
second study measured resveratrol in such muscadine products as wine, unfiltered juice,
pomace and in purees made from pomace. Significant amounts of resveratrol were found in
pomace. Muscadines wines compared favorably in resveratrol concentration with wines
reported in the literature. The consumption of muscadines and muscadine products,
especially those made from pomace purees, could help incorporate a sign
ificant quantity of resveratrol into the average diet.
Many studies suggest that consuming alcohol (especially red wine) may reduce the
incidence of coronary heart disease (CHD). Several studies have demonstrated that
resveratrol is an effective antioxidant. It inhibits lipid peroxidation of low-density
lipoprotein (LDL), prevents the cytotoxicity of oxidized LDL, and protects cells against
lipid peroxidation. It is thought that because it contains highly hydrophilic and
lipophilic properties, it can provide more effective protection than other well-known
antioxidants, such as vitamins C and E. On the other hand, it is less effective than the
antioxidants quercetin and epicatechin found in red wine. Reduced platelet aggregation has
also been demonstrated in studies on resveratrol, further contributing to its prevention
of atherosclerosis. To date, most of the research on resveratrol's antioxidant and
anti-platelet properties has been done in vitro (in an artificial environment using
test-tube or tissue-culture preparations). Further studies in animals and humans
are necessary to determine whether resveratrol supplementation makes sense.
Resveratrol is being studied to see how it affects the initiation,
promotion, and progression of cancer. With regard to tumor initiation,
it has been shown to act as an antioxidant by inhibiting free radical
formation, and as an anti-mutagen in rat models. Resveratrol appears to
decrease tumor promotion activity by inhibiting cyclooxygenase-1
(COX-1), an enzyme that converts arachidonic acid to pro-inflammatory
substances that stimulate tumor-cell growth. Studies related to
progression have found that resveratrol induced human promyelocytic
leukemia cell differentiation and inhibited ribonucleotide reductase,
an enzyme needed for DNA synthesis in proliferating cells. One
appealing characteristic of resveratrol's anti-cancer potential is its
minimal toxicity to blood-forming cells. More studies using both
cellular and animal models are needed before any such data would be
applicable to human use.
The similarity in structure between resveratrol and diethylstilbestrol (a synthetic
estrogen) has prompted investigations into resveratrol's potential as a phytoestrogen (a
plant compound that produces estrogen-like effects). However, these properties also
stimulate the growth of human breast cancer cells. This finding seems contrary to its
other anticancer activities, and is a cause for concern.
A group of Functional Foods for Health (FFH) Program scientists led by Dr. John Pezzuto
in the College of Pharmacy at the UIC campus have recently shown that a substance in
grapes may prevent cancer.
In the study, Pezzuto and colleagues were able to show that resveratrol was effective
during all three phases of the cancer process: initiation, promotion and progression.
Resveratrol was found to have antioxidant and antimutagenic activity and also increased
levels of the phase II drug-metabolizing enzyme quinone reductase, an enzyme capable of
metabolically detoxifying carcinogens, thereby ridding them from the body. All three of
these physiological effects are indicative of resveratrol preventing cancer
initiation--the initial, irreversible stage of the cancer process. Resveratrol also demonstrated antiinflammatory effects and
inhibited the activity of the cyclooxygenase and hydroperoxidase enzymes (suggestive of
antipromotion activity) in addition to causing the differentiation of human promyelocytic
leukemia cells, indicating that this compound may also depress the progression phase of
cancer. Finally, resveratrol inhibited the development of preneoplastic lesions in mouse
mammary glands treated with a carcinogen in culture and inhibited tumor formation in mice.
No toxic effects were observed.
The UIC researchers originally isolated resveratrol from a crude extract of the roots
of a tree collected in Peru under a grant from the National Cancer Institute which
involves screening for cancer-inhibiting compounds from plants. According to Pezzuto, "Of
all the plants we've tested for cancer chemopreventive activity and all the compounds
we've seen, this one has the greatest promise."
See also Flavonoids.html">Flavonoids and Quercetin
- Melissa Q.B. McElderry, M.S., R.D. Grape Expectations: The Resveratrol Story
- Celotti
E. Et al. Resveratrol content of some wines obtained from dried
Valpolicella grapes: Recioto and Amarone. Journal of Chromatography A
730(1-2): 47-52, 1996. - Soleas GJ, Diamandis EP, Goldberg
DM. Resveratrol: A molecule whose time has come? And gone? Clinical
Biochemistry 30:91-113, 1997. - Kopp P. Resveratrol, a
phytoestrogen found in red wine. A possible explanation for the
conundrum of the 'French paradox'? European Journal of Endocrinology
138:619-620, 1998. - Jang M. Et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218-220, 1997.
- Ector
B J. Et Al. Resveratrol Concentration In Muscadine Berries, Juice,
Pomace, Purees, Seeds, And Wines. Small Fruits Research Unit. United
States Department of Agriculture Agricultural Research Service - Chanvitayapongs
S, Draczynska-Lusiak B, Sun AY. Amelioration of oxidative stress by
antioxidants and resveratrol in PC12 cells. Neuroreport 8:1499-1502,
1997. - Rotondo S. Et al. Effect of trans-resveratrol, a
natural polyphenolic compound, on human polymorphonuclear leukocyte
function. British Journal of Pharmacology 123:1691-1699, 1998. - Clement
MV. Et al. Chemopreventive agent resveratrol, a natural product derived
from grapes, triggers CD95 signaling-dependent apoptosis in human tumor
cells. Blood 92:996-1002, 1998. - Jang, M., Cai, L., Udeani,
G.O., Slowing, K.V., Thomas, C.F., Beecher, C.W.W., Fong, H.H.S.,
Farnsworth, N.R., Kinghorn, A.D., Mehta, R.G., Moon, R.C. and Pezzuto,
J.M. Science volume 10:218-221, 1997
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