Biomarker studies is the latest focus of the pharmaceutical and biotech worlds. So much might be learned by looking at how drugs and natural products/ingredients affect the body. Per Wiki, a biomarker is explained as: “in medicine, a biomarker can be a substance that is introduced into an organism as a means to examine organ function or other aspects of health. For example, rubidium chloride is used as a radioactive isotope to evaluate perfusion of heart muscle.
It can also be a substance whose detection indicates a particular disease state, for example, the presence of an antibody may indicate an infection (see biomarker (medicine) ). More specifically, a biomarker indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment. Once a proposed biomarker has been validated, it can be used to diagnose disease risk, presence of disease in an individual, or to tailor treatments for the disease in an individual (choices of drug treatment or administration regimes). In evaluating potential drug therapies, a biomarker may be used as a surrogate for a natural endpoint such as survival or irreversible morbidity. If a treatment alters the biomarker, which has a direct connection to improved health, the biomarker serves as a surrogate endpoint for evaluating clinical benefit.”
A Phase 1 study published in Cancer Epidemoil Biomarkers Prevention in 2007 studied resveratrol in healthy volunteers. Phase 1 trials are typically the first trials in which a drug is tested in a human volunteer. The volunteer can be healthy or have the disease that is being studied. The hypothesis of this study “was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol.” Resveratrol was provided to a small sample size of 10 healthy volunteers in a 0.5, 1, 2.5, or5 g dose format.
“The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation.”
Here is a website that list some studies of resveratrol: http://www.anyvitamins.com/resveratrol-references.htm . Unfortunately, it only lists the studies with no results.
There currently eight registered on-going trials:
New York’s Mount Sinai School of Medicine’s Alzheimer’s Disease Research Center is currently recruiting subjects for their study of resveratrol and alzheimer http://www.delay-ad.org/trials/resveratrol . The University of California is recruiting subjects to perform clinical trials ”to define the actions of resveratrol on the Wnt signaling pathway in a clinical trial in which patients with colon cancer will receive treatment with resveratrol and correlative laboratory studies will examine its effects directly on colon cancer and normal colonic mucosa. These studies will provide data on the mechanisms of resveratrol action and provide a foundation for future prevention trials, correlative studies and therapeutic clinical research with this agent.” http://clinicaltrials.gov/ct2/show/NCT00256334?term=resveratrol&rank=2
For a complete list of the eight trials registered under the government, refer to this link: http://clinicaltrials.gov/ct2/results?term=resveratrol .
Based on researching more about Resveatrol, stay clear of claims of free trials of the product especially if seen on 60 Minutes or Oprah. I read many consumers who signed up for the “free offer” only to be charged large amounts and no one to contact to get a refund. I guess it’s marketed under Resveratrol Ultra and under SWM Labs. Read that small print before buying for all the details such as what others wrote as a scam. You can buy Biotivia brand for $24 for a 240 mb bottle (250 mg). I only noticed headaches when I took resveratrol but can’t say for sure it was attributed to the product. Biomarker study is the latest focus of the pharmaceutical and biotech worlds. So much might be learned by looking at how drugs and natural products/ingredients affect the body. Per Wiki, a biomarker is explained as: “in medicine, a biomarker can be a substance that is introduced into an organism as a means to examine organ function or other aspects of health. For example, rubidium chloride is used as a radioactive isotope to evaluate perfusion of heart muscle .
It can also be a substance whose detection indicates a particular disease state, for example, the presence of an antibody may indicate an infection (see biomarker (medicine) ). More specifically, a biomarker indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment. Once a proposed biomarker has been validated, it can be used to diagnose disease risk, presence of disease in an individual, or to tailor treatments for the disease in an individual (choices of drug treatment or administration regimes). In evaluating potential drug therapies, a biomarker may be used as a surrogate for a natural endpoint such as survival or irreversible morbidity. If a treatment alters the biomarker, which has a direct connection to improved health, the biomarker serves as a surrogate endpoint for evaluating clinical benefit.”
A Phase 1 study published in Cancer Epidemoil Biomarkers Prevention in 2007 studied resveratrol in healthy volunteers. Phase 1 trials are typically the first trials in which a drug is tested in a human volunteer. The volunteer can be healthy or have the disease that is being studied. The hypothesis of this study “was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol.” Resveratrol was provided to a small sample size of 10 healthy volunteers in a 0.5, 1, 2.5, or5 g dose format.
“The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation.”
Here is a website that list some studies of resveratrol: http://www.anyvitamins.com/resveratrol-references.htm . Unfortunately, it only lists the studies with no results.
There currently eight registered on-going trials:
New York’s Mount Sinai School of Medicine’s Alzheimer’s Disease Research Center is currently recruiting subjects for their study of resveratrol and alzheimer http://www.delay-ad.org/trials/resveratrol . The University of California is recruiting subjects to perform clinical trials ”to define the actions of resveratrol on the Wnt signaling pathway in a clinical trial in which patients with colon cancer will receive treatment with resveratrol and correlative laboratory studies will examine its effects directly on colon cancer and normal colonic mucosa. These studies will provide data on the mechanisms of resveratrol action and provide a foundation for future prevention trials, correlative studies and therapeutic clinical research with this agent.” http://clinicaltrials.gov/ct2/show/NCT00256334?term=resveratrol&rank=2
For a complete list of the eight trials registered under the government, refer to this link: http://clinicaltrials.gov/ct2/results?term=resveratrol .
Based on researching more about Resveatrol, stay clear of claims of free trials of the product especially if seen on 60 Minutes or Oprah. I read many consumers who signed up for the “free offer” only to be charged large amounts and no one to contact to get a refund. I guess it’s marketed under Resveratrol Ultra and under SWM Labs. Read that small print before buying for all the details such as what others wrote as a scam. You can buy Biotivia brand for $24 for a 240 mb bottle (250 mg). I only noticed headaches when I took resveratrol but can’t say for sure it was attributed to the product.
There are many types of products on Amazon:
Showing posts with label red wine. Show all posts
Showing posts with label red wine. Show all posts
Good Foods for the Skin
Different websites are touting the benefits of eating right on your skin to prevent wrinkles and retain that youthful glow. I have a friend who at 50, looked AMAZING and actually looked like she was 40. She credited this youthful, wrinkless, glowing complexion to eating right, drinking plenty of water and taking many supplements. Either her genes were very good and/or the lifestyle was working because she looked incredible.
Lycopene from processed tomatoes provides a great source of an anti-oxidant and also helps to ward off cancerous cell formations. Lycopene, in high doses, flush out free radicals. Since lycopene is not made in the body, we require products such as tomatoes to acquire it.
“Researchers introduced Lycopene into pre-existing cancer cell cultures and the Lycopene prevented the continued growth of these cultures. This is pretty powerful evidence that the health benefits of eating a tomato are really quite phenomenal. It takes as little as 540 milliliters of liquid tomato product to get the full benefits of Lycopene. This means that a daily glass of tomato juice has the potential to keep a person healthy for life.”
Oysters provides zinc which provides that nice little feature of repairing and renewing our skin called collagen. As we age, we lose that ability.
Blueberries prevent cell damage by also being a source of an anti-oxidant. In 2004, a team led by a USDA chemist found that this natural anti-oxidant may lower blood levels of LDL which is the “bad” cholesterol and triglycerides. The pterostilbene in blueberries is similar to the chemical Resveratrol found in grapes. Another claim for blueberries as an antioxidant is the benefit towards slowing down visual loss due to the extract from blueberries. It’s called anthocyanosides and has been found in clinical studies to slow down visual loss.
”A recent study was done in a Boston laboratory by putting one group of young rats on a blueberry-rich diet and another on regular chow. Then the scientist exposed both groups to 48 hours of concentrated oxygen, stirring up in two days the amount of free radical damage that normally takes 20 rat months, or 75 humans to accumulate. Brain cells in the chow group became less responsive to neurotransmitters associated with short-term memory. The brains of the blueberry stuffed rats did not change. He also found that the fruit prevented the kind of short-term memory loss that comes with aging. Blueberries actually stave off declines in brain cell’s ability to send messages to one another.”
Dark chocolate has many benefits to include providing yet another anti-oxidant source. It increases blood flow to the skin which rehydrates the skin and provides additional sun protection.
Walnuts provides omega-3 and vitamin E which is a natural way to ward off psoriasis and eczema. Omega-3 fatty acids also provide benefits ranging from better mental functioning to cardiovascular protection to an anti-inflammatory benefits in asthma.
Lycopene from processed tomatoes provides a great source of an anti-oxidant and also helps to ward off cancerous cell formations. Lycopene, in high doses, flush out free radicals. Since lycopene is not made in the body, we require products such as tomatoes to acquire it.
“Researchers introduced Lycopene into pre-existing cancer cell cultures and the Lycopene prevented the continued growth of these cultures. This is pretty powerful evidence that the health benefits of eating a tomato are really quite phenomenal. It takes as little as 540 milliliters of liquid tomato product to get the full benefits of Lycopene. This means that a daily glass of tomato juice has the potential to keep a person healthy for life.”
Oysters provides zinc which provides that nice little feature of repairing and renewing our skin called collagen. As we age, we lose that ability.
Blueberries prevent cell damage by also being a source of an anti-oxidant. In 2004, a team led by a USDA chemist found that this natural anti-oxidant may lower blood levels of LDL which is the “bad” cholesterol and triglycerides. The pterostilbene in blueberries is similar to the chemical Resveratrol found in grapes. Another claim for blueberries as an antioxidant is the benefit towards slowing down visual loss due to the extract from blueberries. It’s called anthocyanosides and has been found in clinical studies to slow down visual loss.
”A recent study was done in a Boston laboratory by putting one group of young rats on a blueberry-rich diet and another on regular chow. Then the scientist exposed both groups to 48 hours of concentrated oxygen, stirring up in two days the amount of free radical damage that normally takes 20 rat months, or 75 humans to accumulate. Brain cells in the chow group became less responsive to neurotransmitters associated with short-term memory. The brains of the blueberry stuffed rats did not change. He also found that the fruit prevented the kind of short-term memory loss that comes with aging. Blueberries actually stave off declines in brain cell’s ability to send messages to one another.”
Dark chocolate has many benefits to include providing yet another anti-oxidant source. It increases blood flow to the skin which rehydrates the skin and provides additional sun protection.
Walnuts provides omega-3 and vitamin E which is a natural way to ward off psoriasis and eczema. Omega-3 fatty acids also provide benefits ranging from better mental functioning to cardiovascular protection to an anti-inflammatory benefits in asthma.
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Resveratrol: My Experience & Other Info
I’ve been taking Resveratrol for four days not and starting on Saturday, I have had intermittent strong headaches. Not sure if it’s related or not but skipped yesterday and I woke up without a headache. I took the recommended dose around noon and my headache came back.
Interesting citings about the supplement on wikiflu: http://www.fluwikie.com/pmwiki.php?n=Consequences.Resveratrol
CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
ADVERSE REACTIONS As resveratrol exhibits estrogen-like properties and activates transcription by estrogen receptor that leads to stimulation of cancer cell proliferation, women with estrogen receptor-positive cancers should avoid resveratrol.
DRUG INTERACTIONS Because resveratrol inhibits platelet aggregation, concurrent use of other antiplatelet drugs may increase the risk of bleeding. This could be harmful in Bird Flu patients with hemorrhagic symptoms Since resveratrol inactivates certain enzymes of the CYP450 family, the concentration of drugs that are metabolized by the same enzymes may increase in the body.
This was published out of Linus Pauling Institute Micronutrient Information Center:
Summary
Resveratrol is a polyphenolic compound found in grapes, red wine, purple grape juice, peanuts, and some berries. (More Information)
When taken orally, resveratrol appears to be well-absorbed by humans, but its bioavailability is relatively low because it is rapidly metabolized and eliminated. (More Information)
Scientists became interested in exploring potential health benefits of resveratrol when its presence was reported in red wine, leading to speculation that resveratrol might help explain the “French Paradox.” (More Information)
Moderate alcohol consumption has been consistently associated with 20-30% reductions in coronary heart disease risk, but it is not yet clear whether red wine polyphenols, such as resveratrol, confer any additional risk reduction. (More Information)
Although resveratrol can inhibit the growth of cancer cells in culture and in some animal models, it is not known whether high intakes of resveratrol can prevent cancer in humans. (More Information)
Resveratrol administration has increased the lifespans of yeast, worms, fruit flies, fish, and mice fed a high-calorie diet, but it is not known whether resveratrol will have similar effects in humans. (More Information)
At present, relatively little is known about the effects of resveratrol in humans.
Introduction
Resveratrol (3,4′,5-trihydroxystilbene) belongs to a class of polyphenolic compounds called stilbenes (1). Some types of plants produce resveratrol and other stilbenes in response to stress, injury, fungal infection, or ultraviolet (UV) radiation (2). Resveratrol is a fat-soluble compound that occurs in a trans and a cis configuration (see figure 1). Both cis- and trans-resveratrol also occur as glucosides (bound to a glucose molecule). Resveratrol-3-O-beta-glucoside is called piceid (3). Scientists became interested in exploring potential health benefits of resveratrol in 1992 when its presence was first reported in red wine (4), leading to speculation that resveratrol might help explain the “French Paradox” (see Cardiovascular Disease below). More recently, reports on the potential for resveratrol to inhibit the development of cancer (5) and extend lifespan (6) in cell culture and animal models have continued to generate scientific interest.
Metabolism and Bioavailability
Although trans-resveratrol appears to be well-absorbed by humans when taken orally, its bioavailability is relatively low due to its rapid metabolism and elimination (7, . Resveratrol metabolites are primarily detected upon oral exposure to trans-resveratrol. When six healthy men and women took an oral dose of 25 mg of trans-resveratrol, only traces of the unchanged resveratrol were detected in plasma (blood). Plasma concentrations of resveratrol and metabolites peaked around 60 minutes later at concentrations around 2 micromoles/liter (491 micrograms/liter) (7). A study in 12 healthy men administered an oral dose of 25 mg of trans-resveratrol per 70 kg of body weight reported that serum concentration of resveratrol and metabolites peaked at 30 minutes after administration. The concentration of total resveratrol (resveratrol and metabolites) ranged from 416 to 471 micrograms/liter, depending on whether resveratrol was administered in wine, vegetable juice, or grape juice (9). Results of another study suggested that the bioavailability of resveratrol from grape juice, which contains mostly glucosides of resveratrol (piceid), may be even lower than that of trans-resveratrol (10). A recent study reported that bioavailability of trans-resveratrol from red wine did not differ when the wine was consumed with a meal (low- or high-fat) versus on an empty stomach (11).
Information about the bioavailability of resveratrol in humans is important because much of the basic research on resveratrol has been conducted in cultured cells exposed to unmetabolized resveratrol at concentrations that are often 10-100 times greater than peak concentrations observed in human plasma after oral consumption (12). Although cells that line the digestive tract are exposed to unmetabolized resveratrol, research in humans suggests that other tissues are exposed primarily to resveratrol metabolites. Little is known about the biological activity of resveratrol metabolites, and it is not known whether some tissues are capable of converting resveratrol metabolites back to resveratrol (7).
Biological Activities
Direct Antioxidant Activity
In the test tube, resveratrol effectively scavenges (neutralizes) free radicals and other oxidants (13) and inhibits low density lipoprotein (LDL) oxidation (14, 15). However, there is little evidence that resveratrol is an important antioxidant in vivo (16). Upon oral consumption of resveratrol, circulating and intracellular levels of resveratrol in humans are likely to be much lower than that of other important antioxidants, such as vitamin C, uric acid, vitamin E, and glutathione. Moreover, the antioxidant activity of resveratrol metabolites, which comprise most of the circulating resveratrol, may be lower than that of resveratrol.
Estrogenic and Anti-estrogenic Activities
Endogenous estrogens are steroid hormones synthesized by humans and other mammals; these hormones bind to estrogen receptors within cells. The estrogen-receptor complex interacts with unique sequences in DNA (estrogen response elements; EREs) to modulate the expression of estrogen-responsive genes (17). A compound that binds to estrogen receptors and elicits similar responses to endogenous estrogens is considered an estrogen agonist, while a compound that binds estrogen receptors but prevents or inhibits the response elicited by endogenous estrogens is considered an estrogen antagonist. The chemical structure of resveratrol is very similar to that of the synthetic estrogen agonist, diethylstilbestrol (see figure 2), suggesting that resveratrol might also function as an estrogen agonist. However, in cell culture experiments resveratrol acts as an estrogen agonist under some conditions and an estrogen antagonist under other conditions (18, 19). In estrogen receptor-positive breast cancer cells, resveratrol acted as an estrogen agonist in the absence of the endogenous estrogen, 17beta-estradiol, but acted as an estrogen antagonist in the presence of 17beta-estradiol (20, 21). At present, it appears that resveratrol has the potential to act as an estrogen agonist or antagonist depending on such factors as cell type, estrogen receptor isoform (ER alpha or ER beta), and the presence of endogenous estrogens (17).
Biological Activities Related to Cancer Prevention
Effects on Biotransformation Enzymes
Some compounds are not carcinogenic until they have been metabolized in the body by cytochrome P450 enzymes (2). By inhibiting the expression and activity of certain cytochrome P450 enzymes (22, 23), resveratrol could help prevent cancer by decreasing exposure to these activated carcinogens. In contrast, increasing the activity of phase II biotransformation enzymes generally promotes the excretion of potentially toxic or carcinogenic chemicals. Resveratrol has been found to increase the expression and activity of the phase II enzyme NAD(P)H:quinone reductase in cultured cells (5, 24).
Preservation of Normal Cell Cycle Regulation
Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or activation of pathways leading to cell death (apoptosis) if the damage is irreparable (25). Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer. Resveratrol has been found to induce cell cycle arrest when added to cancer cells grown in culture (26).
Inhibition of Proliferation and Induction of Apoptosis
Unlike normal cells, cancer cells proliferate rapidly and are unable to respond to cell death signals that initiate apoptosis. Resveratrol has been found to inhibit proliferation and induce apoptosis in a number of cancer cell lines [reviewed in (2, 27)].
Inhibition of Tumor Invasion and Angiogenesis
Cancerous cells invade normal tissue aided by enzymes called matrix metalloproteinases. Resveratrol has been found to inhibit the activity of at least one type of matrix metalloproteinase (28). To fuel their rapid growth, invasive tumors must also develop new blood vessels by a process known as angiogenesis. Resveratrol has been found to inhibit angiogenesis in vitro (29-31).
Anti-inflammatory Effects
Inflammation promotes cellular proliferation and angiogenesis and inhibits apoptosis (32). Resveratrol has been found to inhibit the activity of several inflammatory enzymes in vitro, including cyclooxygenase and lipoxygenase (33, 34). Resveratrol may also inhibit pro-inflammatory transcription factors, such as NFκB or AP-1 (35, 36)
Biological Activities Related to Cardiovascular Disease Prevention
Inhibition of Vascular Cell Adhesion Molecule Expression
Atherosclerosis is now recognized as an inflammatory disease, and several measures of inflammation are associated with increased risk of myocardial infarction (heart attack) (37). One of the earliest events in the development of atherosclerosis is the recruitment of inflammatory white blood cells from the blood to the arterial wall by vascular cell adhesion molecules (38). Resveratrol has been found to inhibit the expression of adhesion molecules in cultured endothelial cells (39, 40).
Inhibition of Vascular Smooth Muscle Cell Proliferation
The proliferation of vascular smooth muscle cells plays an important role in the progression of atherosclerosis (41). Resveratrol has been found to inhibit the proliferation of vascular smooth muscle cells in culture (42, 43).
Stimulation of Endolethelial Nitric Oxide Synthase (eNOS) Activity
eNOS is an enzyme that catalyzes the formation of nitric oxide (NO) by vascular endothelial cells. NO is needed to maintain arterial relaxation (vasodilation), and impaired NO-dependent vasodilation is associated with increased risk of cardiovascular disease (44). Resveratrol has been found to stimulate eNOS activity in cultured endothelial cells (45, 46).
Inhibition of Platelet Aggregation
Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke, respectively. Resveratrol has been found to inhibit platelet aggregation in vitro (47, 48).
Note: It is important to keep in mind that many of the biological activities discussed above were observed in cells cultured in the presence of resveratrol at higher concentrations than those likely to be achieved in humans consuming resveratrol orally (see Metabolism and Bioavailability above).
Disease Prevention
Cardiovascular Disease
Red Wine Polyphenols
Significant reductions in cardiovascular disease risk have been associated with moderate consumption of alcoholic beverages (49, 50). The “French Paradox”—the observation that mortality from coronary heart disease is relatively low in France despite relatively high levels of dietary saturated fat and cigarette smoking—led to the idea that regular consumption of red wine might provide additional protection from cardiovascular disease (51, 52). Red wine contains resveratrol and even higher levels of flavonoids. These polyphenolic compounds have antioxidant, anti-inflammatory, and other potentially anti-atherogenic effects in the test tube and in some animal models of atherosclerosis (53). However, it is not yet known whether increased consumption of polyphenols from red wine provides any additional protection from cardiovascular disease beyond that associated with its alcohol content (see the separate article on Alcoholic Beverages). The results of epidemiological studies addressing this question have been inconsistent. While some large prospective studies found that wine drinkers were at lower risk of cardiovascular disease than beer or liquor drinkers (54-56), others found no difference (57-59). Socioeconomic and lifestyle differences between people who prefer wine and those who prefer beer or liquor may explain part of the additional benefit observed in some studies. Several studies have found that people who prefer wine tend to have higher incomes, more education, smoke less, and eat more fruits and vegetables and less saturated fat than people who prefer other alcoholic beverages (59-64). Although moderate alcohol consumption has been consistently associated with 20-30% reductions in coronary heart disease risk, it is not yet clear whether red wine polyphenols confer any additional risk reduction. Interestingly, studies that administered alcohol-free red wine to rodents noted improvements in various parameters related to cardiovascular disease (65, 66), and a placebo-controlled human study found that heart disease patients administered red grape polyphenol extract experienced acute improvements in endothelial function (67). However, more studies are needed to determine whether drinking red wine confers any cardiovascular benefit beyond that associated with its alcohol content.
Resveratrol
Resveratrol has been found to exert a number of potentially cardioprotective effects in vitro, including inhibition of platelet aggregation (47, 48, 68), promotion of vasodilation by enhancing the production of NO (46, 69) and inhibition of inflammatory enzymes (34, 70, 71). However, the concentrations of resveratrol required to produce these effects are often higher than those that have been measured in human plasma after oral consumption of resveratrol (7). The results of some animal studies suggest that high oral doses of resveratrol could decrease the risk of thrombosis (clot formation) and atherosclerosis (72, 73), but at least one study found increased atherosclerosis in animals fed resveratrol (74). Although its presence in red wine has stimulated a great deal of interest in the potential for resveratrol to prevent cardiovascular disease, there is currently no convincing evidence that resveratrol has cardioprotective effects in humans, particularly in the amounts present in 1-2 glasses of red wine (see Sources).
Cancer
Resveratrol has been found to inhibit the proliferation of a variety of human cancer cell lines, including those from breast, prostate, stomach, colon, pancreatic, and thyroid cancers (2). In animal models, oral administration of resveratrol inhibited the development of esophageal (75), intestinal (76), and mammary (breast) cancer (20, 77) induced by chemical carcinogens. However, oral resveratrol was not effective in inhibiting the development of lung cancer induced by carcinogens in cigarette smoke (78, 79). The effects of oral resveratrol administration on mice that are genetically predisposed to colon cancer have been mixed (80, 81), and a few studies have documented that oral resveratrol protects against colon cancer development in rats administered the carcinogen, 1,2-dimethylhydrazine (82-84). It is not known whether high intakes of resveratrol can help prevent cancer in humans. Clinical trials are currently underway to address this question and to also determine whether resveratrol might be beneficial in cancer treatment (85). Studies on human metabolism of resveratrol suggest that even very high dietary intakes of resveratrol may not result in tissue levels that are high enough to realize most of the protective effects demonstrated in cell culture studies (7, 12).
Longevity
Caloric restriction is known to extend the lifespans of a number of species, including mammals (86). In yeast, caloric restriction stimulates the activity of an enzyme known as Sir2 (87). Providing resveratrol to yeast increased Sir2 activity in the absence of caloric restriction and extended the replicative lifespan of yeast by 70% (6). Resveratrol feeding also extended the lifespans of worms (C. elegans) and fruit flies (D. melanogaster) by a similar mechanism (88). Additionally, resveratrol dose-dependently increased the lifespan of a vertebrate fish (N. furzeri) (89). However, it is not known whether resveratrol will have similar effects in higher animals. A recent study reported that resveratrol extended lifespan of mice on a high-calorie diet such that their lifespan was similar to that of mice fed a standard diet (90). Although resveratrol increased the activity of the homologous human enzyme (Sirt1) in the test tube (6), it is not known whether resveratrol can extend the human lifespan. Moreover, the resveratrol concentrations required to increase human Sirt1 activity were considerably higher than concentrations that have been measured in human plasma after oral consumption. Interestingly, a recent aging study in mice found that a low dose of dietary resveratrol altered gene expression in heart, brain, and skeletal muscle similar to that induced by caloric restriction (91). Like caloric restriction, resveratrol also blunted the age-related decline in heart function in this study. Clinical trials will be needed to determine if these findings are relevant to humans.
Sources
Food Sources
Resveratrol is found in grapes, wine, grape juice, peanuts, and berries of Vaccinum species, including blueberries, bilberries, and cranberries (92-94). In grapes, resveratrol is found only in the skins (95). The amount of resveratrol in grape skins varies with the grape cultivar, its geographic origin, and exposure to fungal infection (96). The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content. Consequently, white and rosé wines generally contain less resveratrol than red wines (4). Red or purple grape juices may also be good sources of resveratrol (3). The predominant form of resveratrol in grapes and grape juice is trans-resveratrol glucoside (trans-piceid), but wines also contain significant amounts of resveratrol aglycones, thought to be the result of sugar cleavage during fermentation (92). Many wines also contain significant amounts of cis-resveratrol (figure 1), which may be produced during fermentation or released from viniferins (resveratrol polymers) (97). Red wine is a relatively rich source of resveratrol, but other polyphenols are present in red wine at considerably higher concentrations than resveratrol (see the separate article on Flavonoids) (98). The total resveratrol content of some beverages and foods are listed in the tables below. These values should be considered approximate since the resveratrol content of foods and beverages can vary considerably.
Total Resveratrol Content of Wines and Grape Juice (3, 99, 100)
Beverage Total resveratrol (mg/liter) Total resveratrol in a 5-oz glass (mg)
White wines (Spanish) 0.05-1.80 0.01-0.27
Rosé wines (Spanish) 0.43-3.52 0.06-0.53
Red wines (Spanish) 1.92-12.59 0.29-1.89
Red wines (global) 1.98-7.13 0.30-1.07
Red grape juice (Spanish) 1.14-8.69 0.17-1.30
Total Resveratrol Content of Selected Foods (92, 94, 101)
Food
Serving Total resveratrol (mg)
Peanuts (raw) 1 cup (146 g) 0.01-0.26
Peanuts (boiled) 1 cup (180 g) 0.32-1.28
Peanut butter 1 cup (258 g) 0.04-0.13
Red grapes 1 cup (160 g) 0.24-1.25
Supplements
Most resveratrol supplements available in the U.S. contain extracts of the root of Polygonum cuspidatum, also known as Hu Zhang or kojo-kon (102). Red wine extracts and red grape extracts containing resveratrol and other polyphenols are also available in the U.S. as dietary supplements. Resveratrol supplements may contain anywhere from 10-50 mg of resveratrol, but the effective doses for chronic disease prevention in humans are not known.
Safety
Adverse Effects
Resveratrol is not known to be toxic or cause adverse effects in humans, but there have been only a few controlled clinical trials to date. A recent trial that evaluated the safety of oral resveratrol in ten subjects found a single dose up to 5 grams resulted in no serious adverse effects (103). In rats, daily oral administration of trans-resveratrol at doses up to 300 mg/kg of body weight for four weeks resulted in no apparent adverse effects (104, 105).
Pregnancy and Lactation
The safety of resveratrol-containing supplements during pregnancy and lactation has not been established (102). Since no safe level of alcohol consumption has been established at any stage of pregnancy (106), pregnant women should avoid consuming wine as a source of resveratrol.
Estrogen-sensitive Cancers
Until more is known about the estrogenic activity of resveratrol in humans, women with a history of estrogen-sensitive cancers, such as breast, ovarian, and uterine cancers, should avoid resveratrol supplements (see Estrogenic and Anti-estrogenic Activities above).
Drug Interactions
Anticoagulant and Antiplatelet Drugs
Resveratrol has been found to inhibit human platelet aggregation in vitro (48, 107). Theoretically, high intakes of resveratrol (e.g., from supplements) could increase the risk of bleeding when taken with anticoagulant drugs, such as warfarin (Coumadin); antiplatelet drugs, such as clopidogrel (Plavix) and dipyridamole (Persantine); and non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, and others.
Drugs Metabolized by Cytochrome P450 3A4
Resveratrol has been reported to inhibit the activity of cytochrome P450 3A4 (CYP3A4) in vitro (108, 109). Although this interaction has not been reported in humans, high intakes of resveratrol (e.g., from supplements) could theoretically increase the bioavailability and toxicity of drugs that undergo extensive first-pass metabolism by CYP3A4. Drugs known to be metabolized by CYP3A4 include but are not limited to HMG-CoA reductase inhibitors (atorvastatin, lovastatin, and simvastatin), calcium channel antagonists (felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, nimodipine, and verapamil), anti-arrhythmic agents (amiodarone), HIV protease inhibitors (saquinivir), immunosuppressants (cyclosporine and tacrolimus), antihistamines (terfenadine), benzodiazepines (midazolam and triazolam), and drugs used to treat erectile dysfunction (sildenafil).
References
--------------------------------------------------------------------------------
Written in March 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in June 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in May 2008 by:
William P. Steward, M.D., Ph.D.
Professor of Oncology
Co-Director of Cancer Biomarkers and Prevention Group
Department of Oncology
University of Leicester
Copyright 2005-2008 Linus Pauling Institute
--------------------------------------------------------------------------------
Disclaimer
The Linus Pauling Institute Micronutrient Information Center provides scientific information on health aspects of micronutrients and phytochemicals for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.
The information on micronutrients and phytochemicals contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.
Interesting citings about the supplement on wikiflu: http://www.fluwikie.com/pmwiki.php?n=Consequences.Resveratrol
CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
ADVERSE REACTIONS As resveratrol exhibits estrogen-like properties and activates transcription by estrogen receptor that leads to stimulation of cancer cell proliferation, women with estrogen receptor-positive cancers should avoid resveratrol.
DRUG INTERACTIONS Because resveratrol inhibits platelet aggregation, concurrent use of other antiplatelet drugs may increase the risk of bleeding. This could be harmful in Bird Flu patients with hemorrhagic symptoms Since resveratrol inactivates certain enzymes of the CYP450 family, the concentration of drugs that are metabolized by the same enzymes may increase in the body.
This was published out of Linus Pauling Institute Micronutrient Information Center:
Summary
Resveratrol is a polyphenolic compound found in grapes, red wine, purple grape juice, peanuts, and some berries. (More Information)
When taken orally, resveratrol appears to be well-absorbed by humans, but its bioavailability is relatively low because it is rapidly metabolized and eliminated. (More Information)
Scientists became interested in exploring potential health benefits of resveratrol when its presence was reported in red wine, leading to speculation that resveratrol might help explain the “French Paradox.” (More Information)
Moderate alcohol consumption has been consistently associated with 20-30% reductions in coronary heart disease risk, but it is not yet clear whether red wine polyphenols, such as resveratrol, confer any additional risk reduction. (More Information)
Although resveratrol can inhibit the growth of cancer cells in culture and in some animal models, it is not known whether high intakes of resveratrol can prevent cancer in humans. (More Information)
Resveratrol administration has increased the lifespans of yeast, worms, fruit flies, fish, and mice fed a high-calorie diet, but it is not known whether resveratrol will have similar effects in humans. (More Information)
At present, relatively little is known about the effects of resveratrol in humans.
Introduction
Resveratrol (3,4′,5-trihydroxystilbene) belongs to a class of polyphenolic compounds called stilbenes (1). Some types of plants produce resveratrol and other stilbenes in response to stress, injury, fungal infection, or ultraviolet (UV) radiation (2). Resveratrol is a fat-soluble compound that occurs in a trans and a cis configuration (see figure 1). Both cis- and trans-resveratrol also occur as glucosides (bound to a glucose molecule). Resveratrol-3-O-beta-glucoside is called piceid (3). Scientists became interested in exploring potential health benefits of resveratrol in 1992 when its presence was first reported in red wine (4), leading to speculation that resveratrol might help explain the “French Paradox” (see Cardiovascular Disease below). More recently, reports on the potential for resveratrol to inhibit the development of cancer (5) and extend lifespan (6) in cell culture and animal models have continued to generate scientific interest.
Metabolism and Bioavailability
Although trans-resveratrol appears to be well-absorbed by humans when taken orally, its bioavailability is relatively low due to its rapid metabolism and elimination (7, . Resveratrol metabolites are primarily detected upon oral exposure to trans-resveratrol. When six healthy men and women took an oral dose of 25 mg of trans-resveratrol, only traces of the unchanged resveratrol were detected in plasma (blood). Plasma concentrations of resveratrol and metabolites peaked around 60 minutes later at concentrations around 2 micromoles/liter (491 micrograms/liter) (7). A study in 12 healthy men administered an oral dose of 25 mg of trans-resveratrol per 70 kg of body weight reported that serum concentration of resveratrol and metabolites peaked at 30 minutes after administration. The concentration of total resveratrol (resveratrol and metabolites) ranged from 416 to 471 micrograms/liter, depending on whether resveratrol was administered in wine, vegetable juice, or grape juice (9). Results of another study suggested that the bioavailability of resveratrol from grape juice, which contains mostly glucosides of resveratrol (piceid), may be even lower than that of trans-resveratrol (10). A recent study reported that bioavailability of trans-resveratrol from red wine did not differ when the wine was consumed with a meal (low- or high-fat) versus on an empty stomach (11).
Information about the bioavailability of resveratrol in humans is important because much of the basic research on resveratrol has been conducted in cultured cells exposed to unmetabolized resveratrol at concentrations that are often 10-100 times greater than peak concentrations observed in human plasma after oral consumption (12). Although cells that line the digestive tract are exposed to unmetabolized resveratrol, research in humans suggests that other tissues are exposed primarily to resveratrol metabolites. Little is known about the biological activity of resveratrol metabolites, and it is not known whether some tissues are capable of converting resveratrol metabolites back to resveratrol (7).
Biological Activities
Direct Antioxidant Activity
In the test tube, resveratrol effectively scavenges (neutralizes) free radicals and other oxidants (13) and inhibits low density lipoprotein (LDL) oxidation (14, 15). However, there is little evidence that resveratrol is an important antioxidant in vivo (16). Upon oral consumption of resveratrol, circulating and intracellular levels of resveratrol in humans are likely to be much lower than that of other important antioxidants, such as vitamin C, uric acid, vitamin E, and glutathione. Moreover, the antioxidant activity of resveratrol metabolites, which comprise most of the circulating resveratrol, may be lower than that of resveratrol.
Estrogenic and Anti-estrogenic Activities
Endogenous estrogens are steroid hormones synthesized by humans and other mammals; these hormones bind to estrogen receptors within cells. The estrogen-receptor complex interacts with unique sequences in DNA (estrogen response elements; EREs) to modulate the expression of estrogen-responsive genes (17). A compound that binds to estrogen receptors and elicits similar responses to endogenous estrogens is considered an estrogen agonist, while a compound that binds estrogen receptors but prevents or inhibits the response elicited by endogenous estrogens is considered an estrogen antagonist. The chemical structure of resveratrol is very similar to that of the synthetic estrogen agonist, diethylstilbestrol (see figure 2), suggesting that resveratrol might also function as an estrogen agonist. However, in cell culture experiments resveratrol acts as an estrogen agonist under some conditions and an estrogen antagonist under other conditions (18, 19). In estrogen receptor-positive breast cancer cells, resveratrol acted as an estrogen agonist in the absence of the endogenous estrogen, 17beta-estradiol, but acted as an estrogen antagonist in the presence of 17beta-estradiol (20, 21). At present, it appears that resveratrol has the potential to act as an estrogen agonist or antagonist depending on such factors as cell type, estrogen receptor isoform (ER alpha or ER beta), and the presence of endogenous estrogens (17).
Biological Activities Related to Cancer Prevention
Effects on Biotransformation Enzymes
Some compounds are not carcinogenic until they have been metabolized in the body by cytochrome P450 enzymes (2). By inhibiting the expression and activity of certain cytochrome P450 enzymes (22, 23), resveratrol could help prevent cancer by decreasing exposure to these activated carcinogens. In contrast, increasing the activity of phase II biotransformation enzymes generally promotes the excretion of potentially toxic or carcinogenic chemicals. Resveratrol has been found to increase the expression and activity of the phase II enzyme NAD(P)H:quinone reductase in cultured cells (5, 24).
Preservation of Normal Cell Cycle Regulation
Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or activation of pathways leading to cell death (apoptosis) if the damage is irreparable (25). Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer. Resveratrol has been found to induce cell cycle arrest when added to cancer cells grown in culture (26).
Inhibition of Proliferation and Induction of Apoptosis
Unlike normal cells, cancer cells proliferate rapidly and are unable to respond to cell death signals that initiate apoptosis. Resveratrol has been found to inhibit proliferation and induce apoptosis in a number of cancer cell lines [reviewed in (2, 27)].
Inhibition of Tumor Invasion and Angiogenesis
Cancerous cells invade normal tissue aided by enzymes called matrix metalloproteinases. Resveratrol has been found to inhibit the activity of at least one type of matrix metalloproteinase (28). To fuel their rapid growth, invasive tumors must also develop new blood vessels by a process known as angiogenesis. Resveratrol has been found to inhibit angiogenesis in vitro (29-31).
Anti-inflammatory Effects
Inflammation promotes cellular proliferation and angiogenesis and inhibits apoptosis (32). Resveratrol has been found to inhibit the activity of several inflammatory enzymes in vitro, including cyclooxygenase and lipoxygenase (33, 34). Resveratrol may also inhibit pro-inflammatory transcription factors, such as NFκB or AP-1 (35, 36)
Biological Activities Related to Cardiovascular Disease Prevention
Inhibition of Vascular Cell Adhesion Molecule Expression
Atherosclerosis is now recognized as an inflammatory disease, and several measures of inflammation are associated with increased risk of myocardial infarction (heart attack) (37). One of the earliest events in the development of atherosclerosis is the recruitment of inflammatory white blood cells from the blood to the arterial wall by vascular cell adhesion molecules (38). Resveratrol has been found to inhibit the expression of adhesion molecules in cultured endothelial cells (39, 40).
Inhibition of Vascular Smooth Muscle Cell Proliferation
The proliferation of vascular smooth muscle cells plays an important role in the progression of atherosclerosis (41). Resveratrol has been found to inhibit the proliferation of vascular smooth muscle cells in culture (42, 43).
Stimulation of Endolethelial Nitric Oxide Synthase (eNOS) Activity
eNOS is an enzyme that catalyzes the formation of nitric oxide (NO) by vascular endothelial cells. NO is needed to maintain arterial relaxation (vasodilation), and impaired NO-dependent vasodilation is associated with increased risk of cardiovascular disease (44). Resveratrol has been found to stimulate eNOS activity in cultured endothelial cells (45, 46).
Inhibition of Platelet Aggregation
Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke, respectively. Resveratrol has been found to inhibit platelet aggregation in vitro (47, 48).
Note: It is important to keep in mind that many of the biological activities discussed above were observed in cells cultured in the presence of resveratrol at higher concentrations than those likely to be achieved in humans consuming resveratrol orally (see Metabolism and Bioavailability above).
Disease Prevention
Cardiovascular Disease
Red Wine Polyphenols
Significant reductions in cardiovascular disease risk have been associated with moderate consumption of alcoholic beverages (49, 50). The “French Paradox”—the observation that mortality from coronary heart disease is relatively low in France despite relatively high levels of dietary saturated fat and cigarette smoking—led to the idea that regular consumption of red wine might provide additional protection from cardiovascular disease (51, 52). Red wine contains resveratrol and even higher levels of flavonoids. These polyphenolic compounds have antioxidant, anti-inflammatory, and other potentially anti-atherogenic effects in the test tube and in some animal models of atherosclerosis (53). However, it is not yet known whether increased consumption of polyphenols from red wine provides any additional protection from cardiovascular disease beyond that associated with its alcohol content (see the separate article on Alcoholic Beverages). The results of epidemiological studies addressing this question have been inconsistent. While some large prospective studies found that wine drinkers were at lower risk of cardiovascular disease than beer or liquor drinkers (54-56), others found no difference (57-59). Socioeconomic and lifestyle differences between people who prefer wine and those who prefer beer or liquor may explain part of the additional benefit observed in some studies. Several studies have found that people who prefer wine tend to have higher incomes, more education, smoke less, and eat more fruits and vegetables and less saturated fat than people who prefer other alcoholic beverages (59-64). Although moderate alcohol consumption has been consistently associated with 20-30% reductions in coronary heart disease risk, it is not yet clear whether red wine polyphenols confer any additional risk reduction. Interestingly, studies that administered alcohol-free red wine to rodents noted improvements in various parameters related to cardiovascular disease (65, 66), and a placebo-controlled human study found that heart disease patients administered red grape polyphenol extract experienced acute improvements in endothelial function (67). However, more studies are needed to determine whether drinking red wine confers any cardiovascular benefit beyond that associated with its alcohol content.
Resveratrol
Resveratrol has been found to exert a number of potentially cardioprotective effects in vitro, including inhibition of platelet aggregation (47, 48, 68), promotion of vasodilation by enhancing the production of NO (46, 69) and inhibition of inflammatory enzymes (34, 70, 71). However, the concentrations of resveratrol required to produce these effects are often higher than those that have been measured in human plasma after oral consumption of resveratrol (7). The results of some animal studies suggest that high oral doses of resveratrol could decrease the risk of thrombosis (clot formation) and atherosclerosis (72, 73), but at least one study found increased atherosclerosis in animals fed resveratrol (74). Although its presence in red wine has stimulated a great deal of interest in the potential for resveratrol to prevent cardiovascular disease, there is currently no convincing evidence that resveratrol has cardioprotective effects in humans, particularly in the amounts present in 1-2 glasses of red wine (see Sources).
Cancer
Resveratrol has been found to inhibit the proliferation of a variety of human cancer cell lines, including those from breast, prostate, stomach, colon, pancreatic, and thyroid cancers (2). In animal models, oral administration of resveratrol inhibited the development of esophageal (75), intestinal (76), and mammary (breast) cancer (20, 77) induced by chemical carcinogens. However, oral resveratrol was not effective in inhibiting the development of lung cancer induced by carcinogens in cigarette smoke (78, 79). The effects of oral resveratrol administration on mice that are genetically predisposed to colon cancer have been mixed (80, 81), and a few studies have documented that oral resveratrol protects against colon cancer development in rats administered the carcinogen, 1,2-dimethylhydrazine (82-84). It is not known whether high intakes of resveratrol can help prevent cancer in humans. Clinical trials are currently underway to address this question and to also determine whether resveratrol might be beneficial in cancer treatment (85). Studies on human metabolism of resveratrol suggest that even very high dietary intakes of resveratrol may not result in tissue levels that are high enough to realize most of the protective effects demonstrated in cell culture studies (7, 12).
Longevity
Caloric restriction is known to extend the lifespans of a number of species, including mammals (86). In yeast, caloric restriction stimulates the activity of an enzyme known as Sir2 (87). Providing resveratrol to yeast increased Sir2 activity in the absence of caloric restriction and extended the replicative lifespan of yeast by 70% (6). Resveratrol feeding also extended the lifespans of worms (C. elegans) and fruit flies (D. melanogaster) by a similar mechanism (88). Additionally, resveratrol dose-dependently increased the lifespan of a vertebrate fish (N. furzeri) (89). However, it is not known whether resveratrol will have similar effects in higher animals. A recent study reported that resveratrol extended lifespan of mice on a high-calorie diet such that their lifespan was similar to that of mice fed a standard diet (90). Although resveratrol increased the activity of the homologous human enzyme (Sirt1) in the test tube (6), it is not known whether resveratrol can extend the human lifespan. Moreover, the resveratrol concentrations required to increase human Sirt1 activity were considerably higher than concentrations that have been measured in human plasma after oral consumption. Interestingly, a recent aging study in mice found that a low dose of dietary resveratrol altered gene expression in heart, brain, and skeletal muscle similar to that induced by caloric restriction (91). Like caloric restriction, resveratrol also blunted the age-related decline in heart function in this study. Clinical trials will be needed to determine if these findings are relevant to humans.
Sources
Food Sources
Resveratrol is found in grapes, wine, grape juice, peanuts, and berries of Vaccinum species, including blueberries, bilberries, and cranberries (92-94). In grapes, resveratrol is found only in the skins (95). The amount of resveratrol in grape skins varies with the grape cultivar, its geographic origin, and exposure to fungal infection (96). The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content. Consequently, white and rosé wines generally contain less resveratrol than red wines (4). Red or purple grape juices may also be good sources of resveratrol (3). The predominant form of resveratrol in grapes and grape juice is trans-resveratrol glucoside (trans-piceid), but wines also contain significant amounts of resveratrol aglycones, thought to be the result of sugar cleavage during fermentation (92). Many wines also contain significant amounts of cis-resveratrol (figure 1), which may be produced during fermentation or released from viniferins (resveratrol polymers) (97). Red wine is a relatively rich source of resveratrol, but other polyphenols are present in red wine at considerably higher concentrations than resveratrol (see the separate article on Flavonoids) (98). The total resveratrol content of some beverages and foods are listed in the tables below. These values should be considered approximate since the resveratrol content of foods and beverages can vary considerably.
Total Resveratrol Content of Wines and Grape Juice (3, 99, 100)
Beverage Total resveratrol (mg/liter) Total resveratrol in a 5-oz glass (mg)
White wines (Spanish) 0.05-1.80 0.01-0.27
Rosé wines (Spanish) 0.43-3.52 0.06-0.53
Red wines (Spanish) 1.92-12.59 0.29-1.89
Red wines (global) 1.98-7.13 0.30-1.07
Red grape juice (Spanish) 1.14-8.69 0.17-1.30
Total Resveratrol Content of Selected Foods (92, 94, 101)
Food
Serving Total resveratrol (mg)
Peanuts (raw) 1 cup (146 g) 0.01-0.26
Peanuts (boiled) 1 cup (180 g) 0.32-1.28
Peanut butter 1 cup (258 g) 0.04-0.13
Red grapes 1 cup (160 g) 0.24-1.25
Supplements
Most resveratrol supplements available in the U.S. contain extracts of the root of Polygonum cuspidatum, also known as Hu Zhang or kojo-kon (102). Red wine extracts and red grape extracts containing resveratrol and other polyphenols are also available in the U.S. as dietary supplements. Resveratrol supplements may contain anywhere from 10-50 mg of resveratrol, but the effective doses for chronic disease prevention in humans are not known.
Safety
Adverse Effects
Resveratrol is not known to be toxic or cause adverse effects in humans, but there have been only a few controlled clinical trials to date. A recent trial that evaluated the safety of oral resveratrol in ten subjects found a single dose up to 5 grams resulted in no serious adverse effects (103). In rats, daily oral administration of trans-resveratrol at doses up to 300 mg/kg of body weight for four weeks resulted in no apparent adverse effects (104, 105).
Pregnancy and Lactation
The safety of resveratrol-containing supplements during pregnancy and lactation has not been established (102). Since no safe level of alcohol consumption has been established at any stage of pregnancy (106), pregnant women should avoid consuming wine as a source of resveratrol.
Estrogen-sensitive Cancers
Until more is known about the estrogenic activity of resveratrol in humans, women with a history of estrogen-sensitive cancers, such as breast, ovarian, and uterine cancers, should avoid resveratrol supplements (see Estrogenic and Anti-estrogenic Activities above).
Drug Interactions
Anticoagulant and Antiplatelet Drugs
Resveratrol has been found to inhibit human platelet aggregation in vitro (48, 107). Theoretically, high intakes of resveratrol (e.g., from supplements) could increase the risk of bleeding when taken with anticoagulant drugs, such as warfarin (Coumadin); antiplatelet drugs, such as clopidogrel (Plavix) and dipyridamole (Persantine); and non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, and others.
Drugs Metabolized by Cytochrome P450 3A4
Resveratrol has been reported to inhibit the activity of cytochrome P450 3A4 (CYP3A4) in vitro (108, 109). Although this interaction has not been reported in humans, high intakes of resveratrol (e.g., from supplements) could theoretically increase the bioavailability and toxicity of drugs that undergo extensive first-pass metabolism by CYP3A4. Drugs known to be metabolized by CYP3A4 include but are not limited to HMG-CoA reductase inhibitors (atorvastatin, lovastatin, and simvastatin), calcium channel antagonists (felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, nimodipine, and verapamil), anti-arrhythmic agents (amiodarone), HIV protease inhibitors (saquinivir), immunosuppressants (cyclosporine and tacrolimus), antihistamines (terfenadine), benzodiazepines (midazolam and triazolam), and drugs used to treat erectile dysfunction (sildenafil).
References
--------------------------------------------------------------------------------
Written in March 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in June 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in May 2008 by:
William P. Steward, M.D., Ph.D.
Professor of Oncology
Co-Director of Cancer Biomarkers and Prevention Group
Department of Oncology
University of Leicester
Copyright 2005-2008 Linus Pauling Institute
--------------------------------------------------------------------------------
Disclaimer
The Linus Pauling Institute Micronutrient Information Center provides scientific information on health aspects of micronutrients and phytochemicals for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.
The information on micronutrients and phytochemicals contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.
