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Resveratrol

Resveratrol

Overview
Resveratrol is a stilbenoid, a type of natural phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...

, and a phytoalexin
Phytoalexin
Phytoalexins are antimicrobial substances synthesized de novo by plants that accumulate rapidly at areas of incompatible pathogen infection. They are broad spectrum inhibitors and are chemically diverse with different types characteristic of particular plant species...

 produced naturally by several plants when under attack by pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s such as bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 or fungi.

The effects of resveratrol are currently a topic of numerous animal and human studies. Its effects on the lifespan of many model organisms remain controversial, with uncertain effects in fruit flies
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

, nematode worms
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

, and short-lived fish. In mouse and rat experiments, anticancer, anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

, blood sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported.
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Encyclopedia
Resveratrol is a stilbenoid, a type of natural phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...

, and a phytoalexin
Phytoalexin
Phytoalexins are antimicrobial substances synthesized de novo by plants that accumulate rapidly at areas of incompatible pathogen infection. They are broad spectrum inhibitors and are chemically diverse with different types characteristic of particular plant species...

 produced naturally by several plants when under attack by pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s such as bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 or fungi.

The effects of resveratrol are currently a topic of numerous animal and human studies. Its effects on the lifespan of many model organisms remain controversial, with uncertain effects in fruit flies
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

, nematode worms
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

, and short-lived fish. In mouse and rat experiments, anticancer, anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

, blood sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. These results have yet to be replicated in humans.

In one positive human trial, extremely high doses (3–5 g) of resveratrol, in a proprietary formulation designed to enhance its bioavailability, significantly lowered blood sugar. This 28-day Phase 1b study was conducted privately in India by pharmaceutical company Sirtris
Sirtris Pharmaceuticals
Sirtris Pharmaceuticals, Inc. is a biotechnology company based in Cambridge, MA that is developing therapies for type 2 diabetes, cancer, and other diseases. Founded in 2004 by a Harvard University biologist, Drs. David Sinclair, and venture capitalist Christoph Westphal, the company went public in...

, and was announced at an investors conference in 2008. However, although it has been alluded to in review articles, the study itself has never been published in a peer-reviewed scientific publication. Despite the mainstream press alleging resveratrol's anti-aging effects, there are no accepted data to form a scientific basis for the application of these claims to mammals (see life extension
Life extension
Life extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...

 section below). At the present time, research on resveratrol is in its infancy and the long-term effects of supplementation in humans are not known.

Resveratrol is found in the skin of red grapes and in other fruits. However, red wine contains very little of it, in the order of one milligram per glass. Resveratrol has also been produced by chemical synthesis and by biotechnological synthesis (metabolic engineered microorganisms) and is sold as a nutritional supplement derived primarily from Japanese knotweed
Japanese knotweed
Japanese Knotweed is a large, herbaceous perennial plant, native to eastern Asia in Japan, China and Korea...

.

Discovery and name


Resveratrol was initially mentioned in a Japanese article in 1939 by M. Takaoka, who isolated it from the poisonous but medicinal Veratrum album
Veratrum album
Veratrum album, commonly known as the False Helleborine Veratrum album, commonly known as the False Helleborine Veratrum album, commonly known as the False Helleborine (also known as White Hellebore, European White Hellebore, White Veratrum; syn...

, variety grandiflorum. The name presumably comes from the fact that it is a resorcinol
Resorcinol
Resorcinol is a dihydroxy benzene. It is the 1,3-isomer of benzenediol with the formula C6H42.-Nomenclature:Benzene-1,3-diol is the name recommended by the International Union of Pure and Applied Chemistry in its 1993 Recommendations for the Nomenclature of Organic Chemistry.-Production:It is...

 derivative coming from a Veratrum
Veratrum
Veratrum is a genus of coarse, highly poisonous perennial herbs of the Melanthiaceae family. In English they are known as the False hellebores or corn lilies. Members of Veratrum are known both in western herbalism and traditional Chinese medicine as toxic herbs to be used with great caution...

species.

Life extension


The groups of Howitz and Sinclair reported in 2003 in the journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...

that resveratrol significantly extends the lifespan of the yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...

 Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...

. Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

and the fruit fly Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

. In 2007, a different group of researchers were able to reproduce Sinclair's results with C. elegans, but a third group could not achieve consistent increases in lifespan of either D. melanogaster or C. elegans.

In 2006, Italian scientists obtained the first positive result of resveratrol supplementation in a vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...

. Using a short-lived fish, Nothobranchius furzeri
Nothobranchius furzeri
The turquoise killifish is a species of fish in the Aplocheilidae branch of the Cyprinodontiformes order. This annual fish inhabits ephemeral pools in semi-arid areas with scarce and erratic precipitations and have adapted to the routine drying of their environment by evolving...

, with a median life span of nine weeks, they found a maximal dose of resveratrol increased the median lifespan by 56%. Compared with the control fish at nine weeks, that is by the end of control fish's life, the fish supplemented with resveratrol showed significantly higher general swimming activity and better learning to avoid an unpleasant stimulus. The authors noted a slight increase of mortality in young fish caused by resveratrol, and hypothesized its weak toxic action stimulated the defense mechanisms and resulted in the life span extension.

Later the same year, Sinclair reported resveratrol counteracted the detrimental effects of a high-fat diet in mice. The high-fat diet was compounded by adding hydrogenated coconut oil
Coconut oil
Coconut oil is an edible oil extracted from the kernel or meat of matured coconuts harvested from the coconut palm . Throughout the tropical world, it has provided the primary source of fat in the diets of millions of people for generations. It has various applications in food, medicine, and industry...

 to the standard diet; it provided 60% of energy from fat, and the mice on it consumed about 30% more calories than the mice on standard diet and became obese and diabetic. Mice on the high-fat diet exhibited a high mortality rate compared to mice fed the standard diet; mice fed the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet alone, making their death rates similar to those on the standard diet. The supplement also partially corrected a subset of the abnormal gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...

 profile and abnormal insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....

 and glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 metabolism. However, resveratrol supplements did not change the levels of free fatty acids and cholesterol, which were much higher than in the mice on standard diet.

A further study by a group of scientists, which included Sinclair, indicated resveratrol treatment had a range of beneficial effects in elderly mice, but did not increase the longevity of ad libitum
Ad libitum
Ad libitum is Latin for "at one's pleasure"; it is often shortened to "ad lib" or "ad-lib"...

–fed mice when started midlife. Later, the National Institute on Aging
National Institute on Aging
The National Institute on Aging ' is a division of the U.S. National Institutes of Health , located in Baltimore, Maryland.The NIA leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life...

's Interventions Testing Program (ITP) also tested three different doses of resveratrol in mice on a normal diet beginning in young adulthood, and again found no effect on lifespan, even at doses roughly eight times higher than those that had normalized the lifespan of the high-fat-fed, obese mice in the earlier study.

2011 study published in Nature suggested that some of the benefits demonstrated in previous studies were overrepresented. . However this study was immediately challenged , and few experiments were suggested to be of inferior quality .

Cancer prevention


In 1997, Jang reported that topical resveratrol applications prevented skin cancer development in mice treated with a carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...

. There have since been many studies of the anti-cancer activity of resveratrol in animal models.
No results of human clinical trials for cancer have been reported.

Clinical trials to investigate the effects on colon cancer and melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...

 (skin cancer) are currently recruiting patients. However, the study of pharmacokinetics of resveratrol in humans concluded even high doses of resveratrol might be insufficient to achieve resveratrol concentrations required for the systemic prevention of cancer.

This is consistent with the results from the animal cancer models, which indicate the in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

effectiveness of resveratrol is limited by its poor systemic bioavailability. The strongest evidence of anticancer action of resveratrol exists for tumors it can contact directly, such as skin and gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

 tumors. For other cancers, the evidence is uncertain, even if massive doses of resveratrol are used.

Thus, resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors
Esophageal cancer
Esophageal cancer is malignancy of the esophagus. There are various subtypes, primarily squamous cell cancer and adenocarcinoma . Squamous cell cancer arises from the cells that line the upper part of the esophagus...

 in rats treated with a carcinogen.; and in several studies, small doses (0.02–8 mg/kg) of resveratrol, given prophylactically, reduced or prevented the development of intestinal and colon tumors in rats given different carcinogens. Similarly, topical application of resveratrol in mice, both before and after the UVB exposure, inhibited the skin damage and decreased skin cancer incidence. However, oral resveratrol was ineffective in treating mice inoculated with melanoma cells. Resveratrol given orally also had no effect on leukemia and lung cancer; however, injected intraperitoneally
Intraperitoneal injection
Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum . IP injection is more often applied to animals than humans...

, 2.5 or 10 mg/kg of resveratrol slowed the growth of metastatic Lewis lung carcinoma
Lewis lung carcinoma
In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibition of DNA synthesisCannabinoids increase the life span of mice carrying Lewis lung tumors and decrease primary tumor size. There are multiple modes of...

s in mice.

Resveratrol treatment appeared to prevent the development of mammary tumors in animal models; however, it had no effect on the growth of existing tumors. Paradoxically, treatment of prepubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...

s.

All of the aforementioned in vivo studies have been in animal models in which the cancer has been artificially induced by some experimental means. Three other studies have investigated the effect of resveratrol on the risk of cancer in normal mice living out a normal lifespan; all of them have found resveratrol supplementation has no significant effect on the burden of tumors, nor on the rate of cancer death.

Other applications


Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal Cell
Cell (journal)
Cell is a peer-reviewed scientific journal publishing research papers across a broad range of disciplines within the life sciences. Areas covered include molecular biology, cell biology, systems biology, stem cells, developmental biology, genetics and genomics, proteomics, cancer research,...

in November, 2006. Mice fed resveratrol for fifteen weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of the Sirtuin 1
Sirtuin 1
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.SIRT1 stands for sirtuin 1 , referring to the fact that its sirtuin homolog in yeast is Sir2...

 gene.

Nicholas Wade's interview-article with Dr. Auwerx stated the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (175 lb) person, the 400 mg/kg of body weight amount used in Auwerx's mouse study would total 30,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4000 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There are limited human safety data. Long-term safety has not been evaluated in humans.

In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn more energy, indicating the same pathway shown in the lab mice works in humans.

Neuroprotective effects: In November 2008, researchers at the Weill Medical College of Cornell University reported dietary supplementation with resveratrol significantly reduced plaque formation in animal brains, a component of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 and other neurodegenerative diseases. In mice, oral resveratrol produced large reductions in brain plaque in the hypothalamus (-90%), striatum (-89%), and medial cortex (-48%) sections of the brain. In humans, oral doses of resveratrol thoretically may reduce beta amyloid plaque associated with aging changes in the brain. Researchers theorize that one mechanism for plaque eradication is the ability of resveratrol to chelate (bind) copper. The neuroprotective effects have been confirmed in several animal model studies.

Anti-inflammatory effects: The anti-inflammatory effects of resveratrol have been demonstrated in several animal model studies. In a rat model of carrageenan-induced paw edema, resveratrol inhibited both acute and chronic phases of the inflammatory process. Similarly, preincubation with resveratrol decreased arachidonic acid release and COX-2 induction in mouse peritoneal macrophages stimulated with tumor promoter PMA, ROI, or lipopolysaccharides (LPS). In an experimental rabbit inflammatory arthritis model, resveratrol showed promise as a potential therapy for arthritis. When administered to rabbits with induced inflammatory arthritis, resveratrol protected cartilage against the progression of inflammatory arthritis.

Cardioprotective effects: Moderate drinking of red wine has long been known to reduce the risk of heart disease. This is best known as “the French paradox
French paradox
The French Paradox is the observation that French people suffer a relatively low incidence of coronary heart disease, despite having a diet relatively rich in saturated fats...

”. Studies suggest resveratrol in red wine may play an important role in this phenomenon. It achieves the effects by the following functions: (1) Inhibition of vascular cell adhesion molecule expression; (2) Inhibition of vascular smooth muscle cell proliferation; (3) Stimulation of endolethelial nitric oxide synthase (eNOS) Activity; (4) Inhibition of platelet aggregation; (5) Inhibition of LDL peroxidation; The cardioprotective effects of resveratrol are also theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy. A 2011 study
concludes, “Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via the SAFE pathway.”

Antidiabetic effects: Studies have shown resveratrol possesses hypoglycemic and hypolipidemic effects in both streptozotocin
Streptozotocin
Streptozotocin is a naturally occurring chemical that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals...

 (STZ)-induced diabetes rats and STZ-nicotinamide-induced diabetes rats. Resveratrol ameliorates common diabetes symptoms, such as polyphagia
Polyphagia
Polyphagia means "eating too much". It derives from the Greek words πολύς which means "very much", and φαγῶ , verb for "I eat"....

, polydipsia
Polydipsia
Polydipsia is a medical symptom in which the patient displays excessive thirst. The word derives from the Greek πολυδιψία, which is derived from πολύς + δίψα...

, and body weight loss. Other diabetic animal model studies by different researchers have also demonstrated the antidiabetic effects of resveratrol. In human clinical trials, resveratrol has lowered blood sugar levels in both Phase Ib and Phase IIa, conducted by Sirtris Pharmaceuticals
Sirtris Pharmaceuticals
Sirtris Pharmaceuticals, Inc. is a biotechnology company based in Cambridge, MA that is developing therapies for type 2 diabetes, cancer, and other diseases. Founded in 2004 by a Harvard University biologist, Drs. David Sinclair, and venture capitalist Christoph Westphal, the company went public in...

, Inc.

Antiviral effects: Studies show resveratrol inhibits herpes simplex virus
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...

 (HSV) types 1 and 2 replication by inhibition of an early step in the virus replication cycle. In vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

studies in mice found resveratrol inhibits or reduces HSV replication in the vagina and limits extravaginal disease. The skin of resveratrol-treated animals showed no apparent dermal toxicity, such as erythema
Erythema
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...

, scaling, crusting, lichenification, or excoriation. Studies also show resveratrol inhibits varicella-zoster virus, certain influenza viruses, respiratory viruses, and human cytomegalovirus. Furthermore, resveratrol synergistically enhances the anti-HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

-1 activity of several anti-HIV drugs.

Pharmacokinetics



One way of administering resveratrol in humans may be buccal delivery, that is without swallowing, by direct absorption through the inside of the mouth. When one milligram of resveratrol in 50 mL 50% alcohol/ water solution was retained in the mouth for one minute before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form. However, the viability of a buccal delivery method is called into question due to the low aqueous solubility of the molecule. For a drug to be absorbed via the transmucosal membrane, the drug must be in free-form/dissolved. Resveratrol fits the criteria for oral transmucosal dosing, except for this caveat. The low aqueous solubility greatly limits the amount that can be absorbed through the buccal mucosal, and is why the method has not been seriously explored further. All resveratrol that is attempted to be taken buccaly will fail to pass through the mucous membrane of the mouth and be absorbed as an oral dose. However, a need to explore buccal delivery in future pharmaceutical formulations has been expressed.

About 70% of the resveratrol dose given orally as a pill is absorbed; nevertheless, oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

 of resveratrol is low because it is rapidly metabolized in intestines and liver into conjugated
Conjugate acid
Within the Brønsted–Lowry acid-base theory , a conjugate acid is the acid member, HX, of a pair of two compounds that transform into each other by gain or loss of a proton. A conjugate acid can also be seen as the chemical substance that releases, or donates, a proton in the forward chemical...

 forms: glucuronate and sulfonate
Sulfonate
A sulfonate is a salt or ester of a sulfonic acid. It contains the functional group R-SO2O-.- Sulfonate salts:Anions with the general formula RSO2O− are called sulfonates. They are the conjugate bases of sulfonic acids with formula RSO2OH. As sulfonic acids tend to be strong acids, the...

. Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected in the blood after 25 mg oral dose. Even when a very large dose (2.5 and 5 g) was given as an uncoated pill, the concentration of resveratrol in blood failed to reach the level claimed to be necessary for the systemic cancer prevention. A formulation of resveratrol in a chewing gum form is now in production, and this would be expected to achieve much higher blood levels than oral formulations. Resveratrol given in a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached five to eight times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments. However, on May 5, 2010, GlaxoSmithKline (GSK) said it had suspended a small clinical trial of SRT501, a proprietary form of resveratrol, due to safety concerns, and terminated the study on December 2, 2010 [ClinicalTrials.gov Identifier: NCT00920556]. Sirtris Pharmaceuticals, which U.K.-based GlaxoSmithKline bought for $720 million in 2008, was developing the drug. GlaxoSmithKline is now focusing its efforts on more potent and selective SIRT1 activators—SRT2104 and SRT2379—both of which are involved in several exploratory clinical trials.

Full formal pharmacokinetics of oral resveratrol 2000 mg twice daily in humans, studying interaction with concurrent ethanol, quercetin and fat meal has been published. Mean peak serum resveratrol concentration was 1274 ng/mL at steady-state, which was reduced 46% by a fat meal at dosing. There was no effect of concurrent oral quercetin or ethanol. Healthy volunteers had frequently reported minor diarrhea, and laboratory measures identified slight changes in liver function tests, and serum potassium. No adverse effect on renal function was identified, although only eight healthy adults were observed in the two-week study.

In humans and rats, less than 5% of the oral dose is being observed as free resveratrol in blood plasma. The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Walle suggests sulfate conjugates are the primary source of activity, Wang et al. suggests the glucuronides, and Boocock et al. also emphasized the need for further study of the effects of the metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...

s, including the possibility of deconjugation to free resveratrol inside cells. Goldberd, who studied the pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...

 of resveratrol, catechin
Catechin
Catechin is a natural phenol antioxidant plant secondary metabolite. The term catechins is also commonly used to refer to the related family of flavonoids and the subgroup flavan-3-ols ....

 and quercetin
Quercetin
Quercetin , a flavonol, is a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods.-Occurrence:...

 in humans, concluded "it seems that the potential health benefits of these compounds based upon the in vitro activities of the unconjugated compounds are unrealistic and have been greatly exaggerated. Indeed, the profusion of papers describing such activities can legitimately be described as irrelevant and misleading. Henceforth, investigations of this nature should focus upon the potential health benefits of their glucuronide
Glucuronide
A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...

 and sulfate
Sulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...

 conjugates."

The hypothesis that resveratrol from wine could have higher bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

 than resveratrol from a pill has been refuted by experimental data. For example, after five men took 600 mL of red wine with the resveratrol content of 3.2 mg/L (total dose about 2 mg) before breakfast, unchanged resveratrol was detected in the blood of only two of them, and only in trace amounts (below 2.5 ng/mL). Resveratrol levels appeared to be slightly higher if red wine (600 mL of red wine containing 0.6 mg/mL resveratrol; total dose about 0.5 mg) was taken with meal: trace amounts (1–6 ng/mL) were found in four out of ten subjects. In another study, the pharmacokinetics of resveratrol (25 mg) did not change whether it was taken with vegetable juice, white wine or white grape juice. The highest level of unchanged resveratrol in the serum
Serous fluid
In physiology, the term serous fluid is used for various bodily fluids that are typically pale yellow and transparent, and of a benign nature, that fill the inside of body cavities. Serous fluid originates from serous glands, with secretions enriched with proteins and water. Serous fluid may also...

 (7–9 ng/mL) was achieved after 30 minutes, and it completely disappeared from blood after four hours. The authors of both studies concluded the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. The beneficial effects of wine apparently could be explained by the effects of alcohol or the whole complex of substances wine contains; for example, the cardiovascular benefits of wine appear to correlate with the content of procyanidins
Proanthocyanidin
Proanthocyanidins, also known as OPCs or condensed tannins, are a subgroup of the flavonoid class of polyphenols...

.

Adverse effects and unknowns


Long-term effects of using resveratrol are as of yet unknown. One study has theorized it may stimulate the growth of human breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

 cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen. However, other studies have found resveratrol intake is inversely associated with breast cancer risk, and acts to slow the progression of breast cancer that has been transplanted into mice. Some studies suggest resveratrol slows the development of blood vessels, which suppresses tumors, but also slows healing. Citing the evidence that resveratrol is estrogen antagonistic, some retailers of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product, while others advise that resveratrol should not be taken by children or young adults under 18, as no studies have shown how it affects their natural development. A small study found a single dose of up to 5 g of trans-resveratrol caused no serious adverse effects in healthy volunteers.

Possible carcinogenicity



Resveratrol in common with other polyphenols, was found to be a strong topoisomerase inhibitor
Topoisomerase inhibitor
Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes , which are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.In recent years,...

, sharing similarities to chemotherapeutic anticancer drugs, such as etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...

 and doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....

. This may simultaneously contribute to both the potential anticarcinogenic and carcinogenic properties of the substance in given circumstances. Harmful properties of resveratrol may be pronounced in the human fetus, as it has diminished detoxification systems. Therefore, resveratrol as commonly sold combined with other "bioflavonoids", should not be used by pregnant women.

Mechanisms of action


The mechanisms of resveratrol's apparent effects on life extension
Life extension
Life extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...

 are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction
Calorie restriction
Caloric restriction , or calorie restriction, is a dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects...

. Some studies indicates resveratrol activates Sirtuin 1
Sirtuin 1
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.SIRT1 stands for sirtuin 1 , referring to the fact that its sirtuin homolog in yeast is Sir2...

 (SIRT1) and PGC-1α and improves the functioning of the mitochondria. Other research calls into question the theory connecting resveratrol, SIRT1, and calorie restriction. In addition resveratrol's ability to directly activate sirtuin 1 has been called into question.

A paper by Robb et al. discusses resveratrol action in cells. It reports a fourteen-fold increase in the action of MnSOD (SOD2
SOD2
Superoxide dismutase 2, mitochondrial, also known as SOD2, is an enzyme which in humans is encoded by the SOD2 gene.- Function :This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial matrix protein that forms a homotetramer and binds one manganese ion...

). MnSOD reduces superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...

 to hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...

 (H2O2), but H2O2 is not increased due to other cellular activity. Superoxide O2- is a byproduct of respiration in complexes 1 and 3 of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...

. It is "not highly toxic, [but] can extract an electron from biological membrane and other cell components, causing free radical chain reactions. Therefore it is essential for the cell to keep superoxide anions in check." MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction
Mitochondrial disease
Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the organelles that are the "powerhouses" of the cell. Mitochondria are found in every cell of the human body except red blood cells...

, permeability transition, and apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 death in various diseases. It has been implicated in lifespan extension, inhibits cancer, (e.g. pancreatic cancer) and provides resistance to reperfusion injury
Reperfusion injury
Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and...

 and irradiation damage. These effects have also been observed with resveratrol. Robb et al. propose MnSOD is increased by the pathway RESV → SIRT1 / NAD+ → FOXO3a → MnSOD. Resveratrol has been shown to cause SIRT1 to cause migration of FOXO transcription factors to the nucleus which stimulates FOXO3a transcriptional activity and it has been shown to enhance the sirtuin-catalyzed deacetylation (activity) of FOXO3a
FOXO3A
Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.- Function :FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA binding domain. There are three other FoxO family members in...

. MnSOD is known to be a target of FOXO3a, and MnSOD expression is strongly induced in cells overexpressing FOXO3a.

Resveratrol interferes with all three stages of carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...

—initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

 NF-κB, inhibition of the cytochrome P450 isoenzyme CYP1A1
CYP1A1
Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the CYP1A1 gene. The protein is a member of the cytochrome P450 superfamily of enzymes.-Function:...

 (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene), alterations in androgenic actions and expression and activity of cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...

 (COX) enzymes. In vitro, resveratrol "inhibited the proliferation of human pancreatic cancer cell lines." In some lineages of cancer cell culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...

, resveratrol has been shown to induce apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

, which means it kills cells and may kill cancer cells. Resveratrol has been shown to induce Fas/Fas ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

 mediated apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

, p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

 and cyclin
Cyclin
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...

s A, B1 and cyclin-dependent kinase
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...

s cdk 1 and 2. Resveratrol also possesses antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

 and anti-angiogenic properties.

Resveratrol was reported to be effective against neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

al cell dysfunction and cell death, and, in theory, could be effective against diseases such as Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...

 and Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

. Again, this has not yet been tested in humans for any disease.

Research at the Northeastern Ohio Universities College of Medicine
Northeastern Ohio Universities College of Medicine
Northeast Ohio Medical University, also known as NEOMED, and formerly known as the Northeastern Ohio Universities Colleges of Medicine and Pharmacy , is a community-based, public state university that offers a Doctor of Medicine degree and combined B.S./M.D. program, which allows students to...

 and Ohio State University
Ohio State University
The Ohio State University, commonly referred to as Ohio State, is a public research university located in Columbus, Ohio. It was originally founded in 1870 as a land-grant university and is currently the third largest university campus in the United States...

 indicated resveratrol has direct inhibitory action on cardiac fibroblasts, and may inhibit the progression of cardiac
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...

 fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...

.

Resveratrol also significantly increases natural testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

 production from being both a selective estrogen receptor modulator
Selective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...

 and an aromatase inhibitor
Aromatase inhibitor
Aromatase inhibitors are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. AIs may also be used off-label to treat or prevent gynaecomastia in men....

.

In December 2007, work from Irfan Rahman's laboratory at the University of Rochester
University of Rochester
The University of Rochester is a private, nonsectarian, research university in Rochester, New York, United States. The university grants undergraduate and graduate degrees, including doctoral and professional degrees. The university has six schools and various interdisciplinary programs.The...

 demonstrated resveratrol increased intracellular glutathione levels via Nrf2-dependent upregulation of gamma-glutamylcysteine
Gamma-Glutamylcysteine
γ-Glutamylcysteine is a precursor of glutathione. It is formed by gamma-glutamylcysteine synthetase and used by glutathione synthetase to form glutathione....

 ligase in lung epithelial cells, which protected them against cigarette smoke extract-induced oxidative stress.

Another potentially important mechanism common to both resveratrol supplementation and caloric restriction is the modulation of autophagy
Autophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...

 SIRT1 is a hypothesized target of both resveratrol and caloric restriction, and has been shown to facilitate autophagy through the inhibition of mTOR, which itself negatively regulates autophagy.

Chemical and physical properties


Resveratrol (3,5,4'-trihydroxystilbene) is a stilbenoid, a derivate of stilbene.

It exists as two geometric isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. The trans- and cis-resveratrol can be either free or bound to glucose. The trans- form can undergo isomerisation to the cis- form when exposed to ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...

 irradiation. Trans-resveratrol in the powder form was found to be stable under "accelerated stability" conditions of 75% humidity and 40°C in the presence of air. Resveratrol content also was stable in the skins of grapes and pomace
Pomace
Pomace , or marc , is the solid remains of grapes, olives, or other fruit after pressing for juice or oil. It contains the skins, pulp, seeds, and stems of the fruit....

 taken after fermentation and stored for a long period.
lH- and 13C-NMR data for the four most common forms of resveratrols are reported in literature.

Plants and foods


Resveratrol is produced in plants with the help of the enzyme resveratrol synthase.

Resveratrol was originally isolated by Takaoka from the roots of hellebore
Veratrum album
Veratrum album, commonly known as the False Helleborine Veratrum album, commonly known as the False Helleborine Veratrum album, commonly known as the False Helleborine (also known as White Hellebore, European White Hellebore, White Veratrum; syn...

 in 1940, and later, in 1963, from the roots of Japanese knotweed
Japanese knotweed
Japanese Knotweed is a large, herbaceous perennial plant, native to eastern Asia in Japan, China and Korea...

. However, it attracted wider attention only in 1992, when its presence in wine was suggested as the explanation for cardioprotective effects of wine.

In grape, trans-resveratrol is a phytoalexin produced against the growth of fungal pathogens such as Botrytis cinerea
Botrytis cinerea
Botrytis cinerea is a necrotrophic fungus that affects many plant species, although its most notable hosts may be wine grapes. In viticulture, it is commonly known as botrytis bunch rot; in horticulture, it is usually called grey mould or gray mold.The fungus gives rise to two different kinds of...

. Its presence in Vitis vinifera grapes can also be constitutive, with accumulation in ripe berries of different levels of bound and free resveratrols, according to the genotype. In grapes, resveratrol is found primarily in the skin, and, in muscadine
Muscadine
Muscadines are a grapevine species native to the present-day southeastern United States that has been extensively cultivated since the 16th Century. It differs from Vitis spp. in its number of chromosomes and its morphology...

 grapes, also in the seeds. The amount found in grape skins also varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content.

The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/L, depending on the grape variety, while white wine has much less, because red wine is fermented
Fermentation (wine)
The process of fermentation in wine turns grape juice into an alcoholic beverage. During fermentation, yeast interact with sugars in the juice to create ethanol, commonly known as ethyl alcohol, and carbon dioxide...

 with the skins, allowing the wine to extract the resveratrol, whereas white wine is fermented after the skin has been removed. The composition of wine is different from that of grape since the extraction of resveratrols from grape depends on the duration of the skin contact, and the resveratrol 3-glucosides are in part hydrolised, yielding both trans- and cis-resveratrol. A number of reports have indicated muscadine
Muscadine
Muscadines are a grapevine species native to the present-day southeastern United States that has been extensively cultivated since the 16th Century. It differs from Vitis spp. in its number of chromosomes and its morphology...

 grapes may contain high concentrations of resveratrol, and that wines produced from these grapes, both red and white, may contain more than 40 mg/L. However, subsequent studies have found little or no resveratrol in different varieties of muscadine grapes.

One of the most promising sources is peanut
Peanut
The peanut, or groundnut , is a species in the legume or "bean" family , so it is not a nut. The peanut was probably first cultivated in the valleys of Peru. It is an annual herbaceous plant growing tall...

, especially sprouted
Sprouting
Sprouting is the practice of germinating seeds to be eaten either raw or cooked.They are a convenient way to have fresh vegetables for salads, or otherwise, in any season and can be germinated at home or produced industrially...

 peanuts where the content rivals that in grapes. Before sprouting it was in the range of 2.3 to 4.5 μg/g, and after sprouting in the range of 11.7 to 25.7 μg/g depending upon peanut cultivar. Instructions on sprouting peanuts can be found here.

The fruit of the mulberry
Mulberry
Morus is a genus of flowering plants in the family Moraceae. The 10–16 species of deciduous trees it contains are commonly known as Mulberries....

 (esp. the skin) is a source, and sold as a nutritional supplement.

Cocoa powder, baking chocolate and dark chocolate also have low levels of resveratrol in normal consumption quantities (0.35 to 1.85 mg/kg).

Of growing importance is Japanese Knotweed
Japanese knotweed
Japanese Knotweed is a large, herbaceous perennial plant, native to eastern Asia in Japan, China and Korea...

, which is being used by some manufacturers for its high level of resveratrol.

Content in wines and grape juice

Beverage Total resveratrol (mg/L) Total resveratrol (mg/150mL)
Red wine (global) 1.98 - 7.13 0.30 - 1.07
Red wine (Spanish) 1.92 - 12.59 0.29 - 1.89
Red grape juice (Spanish) 1.14 - 8.69 0.17 - 1.30
Rose wine (Spanish) 0.43 - 3.52 0.06 - 0.53
Pinot noir 0.40 - 2.0 0.06 - 0.30
White wine (Spanish) 0.05 - 1.80 0.01 - 0.27


The trans-resveratrol concentration in 40 Tuscan wines ranged from 0.3 to 2.1 mg/L in the 32 red wines tested and had a maximum of 0.1 mg/L in the 8 white wines in the test. Both the cis- and trans-isomers of resveratrol were detected in all tested samples. cis-Resveratrol levels were comparable to those of the trans-isomer. They ranged from 0.5 mg/L to 1.9 mg/L in red wines and had a maximum of 0.2 mg/L in white wines.

In a review of published resveratrol concentrations, the average in red wines is 1.9 ± 1.7 mg trans-resveratrol/L (8.2 ± 7.5 μM), ranging from nondetectable levels to 14.3 mg/L (62.7 μM) trans-resveratrol. Levels of cis-resveratrol follow the same trend as trans-resveratrol.

Reports suggest some aspect of the wine making process converts piceid
Piceid
Piceid is a stilbenoid glucoside and is a major resveratrol derivative in grape juices. It can also be isolated from Polygonum cuspidatum....

 to resveratrol in wine, as wine seems to have twice the average resveratrol concentration of the equivalent commercial juices.

In general, wines made from grapes of the Pinot Noir and St. Laurent varieties showed the highest level of trans-resveratrol, though no wine or region can yet be said to produce wines with significantly higher concentrations than any other wine or region.

Content in selected foods

Food Serving Total resveratrol (mg)
Peanuts (raw) 1 c (146 g) 0.01 - 0.26
Peanuts (boiled) 1 c (180 g) 0.32 - 1.28
Peanut butter 1 c (258 g) 0.04 - 0.13
Red grapes 1 c (160 g) 0.24 - 1.25
Cocoa powder 1 c (200 g) 0.28 - 0.46


Ounce for ounce, peanuts have about half as much resveratrol as red wine. The average amount in peanuts in the marketplace is 79.4 µg/ounce.

In comparison, some red wines contain approximately 160 µg/fluid ounce. Resveratrol was detected in grape, cranberry, and wine samples. Concentrations ranged from 1.56 to 1042 nmol/g in Concord grape products, and from 8.63 to 24.84 µmol/L in Italian red wine. The concentrations of resveratrol were similar in cranberry and grape juice at 1.07 and 1.56 nmol/g, respectively.

Blueberries
Blueberry
Blueberries are flowering plants of the genus Vaccinium with dark-blue berries and are perennial...

 have about twice as much resveratrol as bilberries
Bilberry
Bilberry is any of several species of low-growing shrubs in the genus Vaccinium , bearing edible berries. The species most often referred to is Vaccinium myrtillus L., but there are several other closely related species....

, but there is great regional variation. These fruits have less than 10% of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half.

Supplementation


As a result of extensive news coverage, sales of supplements greatly increased in 2006. This was despite the existence of studies cautioning that benefits to humans are unproven.

Supplements vary in purity, and can contain anywhere from 50 percent to 99 percent resveratrol. Many brands consist of an unpurified extract of Japanese knotweed; these contain about 50 percent resveratrol by weight, as well as emodin
Emodin
Emodin is a purgative resin, 6-methyl-1,3,8-trihydroxyanthraquinone, from rhubarb, the buckthorn and Japanese Knotweed...

, which, while considered safe in moderate quantities, can have a laxative effect
Laxative
Laxatives are foods, compounds, or drugs taken to induce bowel movements or to loosen the stool, most often taken to treat constipation. Certain stimulant, lubricant, and saline laxatives are used to evacuate the colon for rectal and/or bowel examinations, and may be supplemented by enemas under...

 in high amounts.

Harvard University scientist Professor David Sinclair
David Sinclair (biologist)
David A. Sinclair PhD is a biologist best known for his research on the biology of lifespan extension and driving research towards treating diseases of ageing.-Current position:...

 is often quoted in online ads. Sinclair, who has studied resveratrol extensively, has gone on record in Bloomberg Businessweek to say he never uttered many of the statements attributed to him on these sites.

Testosterone


A Korean study showed that trans-resveratrol supplementation increased testosterone levels in men in vivo, which has led to its marketing as a bodybuilding supplement. A Spanish study has also shown the antioxidant to increase sperm production in rats.

Related compounds

  • Epsilon-viniferin
    Epsilon-viniferin
    ε-Viniferin is a naturally occurring polyphenol, belonging to the stilbenoids family. It is found in grapevines, in wines, and in the Oriental medicinal plant Vitis coignetiae.It is a resveratrol dimer.-External links:*...

     and Pallidol
    Pallidol
    Pallidol is a resveratrol dimer. It can be found in red wine, in Cissus pallida or in Parthenocissus laetevirens.-External links:*...

    , two different resveratrol dimers
  • Trans-diptoindonesin B
    Trans-diptoindonesin B
    trans-Diptoindonesin B is an oligomeric stilbenoid.It is a resveratrol trimer. It can be isolated from Dryobalanops oblongifolia....

    , a resveratrol trimer
  • Hopeaphenol
    Hopeaphenol
    Hopeaphenol is a stilbenoid. It is a resveratrol tetramer isolated from wines.It shows an opposite effect to vitisin A on apoptosis of myocytes isolated from adult rat heart....

    , a resveratrol tetramer

  • Piceatannol
    Piceatannol
    Piceatannol is a stilbenoid, a type of phenolic compound. It is a metabolite of resveratrol found in red wine.Astringin is a piceatannol glucoside.-Health effects:...

    , an active metabolite of resveratrol found in red wine
  • Piceid
    Piceid
    Piceid is a stilbenoid glucoside and is a major resveratrol derivative in grape juices. It can also be isolated from Polygonum cuspidatum....

    , a resveratrol glucoside
  • Pterostilbene
    Pterostilbene
    Pterostilbene is a stilbenoid chemically related to resveratrol and is found in blueberries and grapes. It belongs to the group of phytoalexins, agents produced by plants to fight infections. Based on animal studies it is thought to exhibit anti-cancer, anti-hypercholesterolemia,...

    , a doubly methylated resveratrol

See also


  • Japanese knotweed
    Japanese knotweed
    Japanese Knotweed is a large, herbaceous perennial plant, native to eastern Asia in Japan, China and Korea...

  • List of grape varieties
  • Mulberry
    Mulberry
    Morus is a genus of flowering plants in the family Moraceae. The 10–16 species of deciduous trees it contains are commonly known as Mulberries....

  • Muscadine
    Muscadine
    Muscadines are a grapevine species native to the present-day southeastern United States that has been extensively cultivated since the 16th Century. It differs from Vitis spp. in its number of chromosomes and its morphology...

  • Pterostilbene
    Pterostilbene
    Pterostilbene is a stilbenoid chemically related to resveratrol and is found in blueberries and grapes. It belongs to the group of phytoalexins, agents produced by plants to fight infections. Based on animal studies it is thought to exhibit anti-cancer, anti-hypercholesterolemia,...

    , a stilbenoid chemically related to resveratrol
  • Phenolic compounds in wine
    Phenolic compounds in wine
    The phenolic compounds - natural phenol and polyphenols - in wine include a large group of several hundred chemical compounds that affect the taste, color and mouthfeel of wine. These compounds include phenolic acids, stilbenes, flavonols, dihydroflavonols, anthocyanins, flavanol monomers and...

  • Proanthocyanidin
    Proanthocyanidin
    Proanthocyanidins, also known as OPCs or condensed tannins, are a subgroup of the flavonoid class of polyphenols...

  • Polyphenol antioxidant
    Polyphenol antioxidant
    A polyphenol antioxidant is a type of antioxidant containing a polyphenolic substructure. Numbering over 4,000 distinct species, many of these compounds have antioxidant activity in vitro but are unlikely to have antioxidant roles in vivo...

  • Wine and health
    Wine and health
    The issue of wine and health is a topic of considerable discussion and research. Wine has a long history of use as an early form of medication, being recommended variously as a safe alternative to drinking water, an antiseptic for treating wounds and a digestive aid, as well as a cure for a wide...



Further reading


External links