Resveratrol

Resveratrol

Chemical structures of cis- ((Z)-resveratrol, left) and trans-resveratrol ((E)-resveratrol, right)[1]
Names
Other names
trans-3,5,4′-Trihydroxystilbene;
3,4′,5-Stilbenetriol;
trans-Resveratrol;
(E)-5-(p-Hydroxystyryl)resorcinol;
(E)-5-(4-hydroxystyryl)benzene-1,3-diol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.121.386
KEGG
RTECS number CZ8987000
UNII
Properties
C14H12O3
Molar mass 228.25 g·mol−1
Appearance white powder with
slight yellow cast
Melting point 261 to 263 °C (502 to 505 °F; 534 to 536 K)[2]
Solubility in water 0.03 g/L
Solubility in DMSO 16 g/L
Solubility in ethanol 50 g/L
UV-vis (λmax) 304nm (trans-resveratrol, in water)
286nm (cis-resveratrol, in water)[1]
Hazards
Safety data sheet Fisher Scientific[2]
Sigma Aldrich[3]
R-phrases (outdated) R36 (irritating to eyes)[3]
S-phrases (outdated) S26 (in case of contact with eyes, rinse immediately with plenty of water and seek medical advice)[3]
Lethal dose or concentration (LD, LC):
23.2 µM (5.29 g)[4]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
UV visible spectrum of trans-resveratrol

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or, when the plant is under attack by pathogens such as bacteria or fungi.[5][6] Sources of resveratrol in food include the skin of grapes, blueberries, raspberries, mulberries.[7]

Although it is used as a dietary supplement, there is no good evidence that consuming resveratrol affects life expectancy or human health.[8][9]

Health effects

Heart disease

There is no evidence of benefit from resveratrol in those who already have heart disease.[10] A 2014 Chinese meta-analysis found a statistically significant 11.90 mmHg reduction in systolic blood pressure from resveratrol doses of 150 mg/day.[11]

Cancer

As of 2014, there is no evidence of an effect of resveratrol on cancer in humans.[12]

Metabolism

There is no conclusive evidence for an effect of resveratrol on human metabolism.[13][14] Animal studies indicate that resveratrol induces metabolic adaptations in mice associated with an "exercise-trained" state (i.e., higher physical fitness), but clinical studies have found that these effects might not occur in humans.[15]

Lifespan

There is no evidence for an effect of resveratrol on lifespan in humans as of 2011.[16]

Adverse effects

A limited number of human studies have shown resveratrol is generally well-tolerated.[17][14]

A 2018 review of 17 clinical trials on the effects of resveratrol on blood pressure found that one person taking a 1000 mg daily dose developed an itchy rash that resolved after discontinuation, and that in four of the trials, people had increased frequency of bowel movements and loose stools in first month of the trial.[17] In a year long Phase II trial in people with Alzheimers, the most frequent adverse effects were diarrhea, weight loss, and nausea.[18]

Pharmacology

Pharmacodynamics

Resveratrol has been identified as a pan-assay interference compound, which produces positive results in many different laboratory assays.[19] Its ability for varied interactions may be due to direct effects on cell membranes.[20]

As of 2015, many specific biological targets for resveratrol had been identified or identified, including NQO2 (alone and in interaction with AKT1), GSTP1, estrogen receptor beta, CBR1, and integrin αVβ. It was unclear at that time if any or all of these were responsible for the observed effects in cells and model organisms.[21]

In vitro studies indicate resveratrol activates sirtuin 1,[22] although this may be a downstream effect from its immediate biological target(s).[23][24] It appears to signal through PGC-1α, thereby affecting mitochondria.[25] In cells treated with resveratrol, an increase is observed in the action of MnSOD (SOD2)[26] and in GPER activity.[27] In vitro, resveratrol was shown to act as an agonist of Peroxisome proliferator-activated receptor gamma, a nuclear receptor under pharmacological research as a potential treatment for type 2 diabetes.[28]

Pharmacokinetics

One way of administering resveratrol in humans may be buccal delivery, that is without swallowing, by direct absorption through tissues on 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 was 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.[29] 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 transmucosally it must be in free-form or dissolved.[30][31] 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 mucosa. Resveratrol that is attempted to be taken buccally was expected to pass through the mucous membrane of the mouth and be absorbed as an oral dose,[32] however, the need to explore buccal delivery in future pharmaceutical formulations was expressed.[31][33]

While 70% of orally administered resveratrol is absorbed, its oral bioavailability is approximately 0.5% due to extensive hepatic glucuronidation and sulfation.[34] 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.[35]

In a human study involving oral administration of 500 mg over 13 weeks, resveratrol was detected in cerebrospinal fluid,[36] which suggests that it enters the brain via the blood–cerebrospinal fluid barrier.

Metabolism

Resveratrol gets extensively metabolized in the body, with the liver and lungs as the major sites of its metabolism.[37]

Chemistry

Resveratrol (3,5,4'-trihydroxystilbene) is a stilbenoid, a derivative 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.[38]

The trans- form can undergo isomerization to the cis- form when exposed to ultraviolet irradiation,[39] a process called photoisomerization:[40]

Resveratrol photoisomerization

One study showed that ultraviolet irradiation to cis-resveratrol induces further photochemical reaction, producing a fluorescent molecule named "Resveratrone".[41]

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.[42] The trans isomer is also stabilized by the presence of transport proteins.[43] Resveratrol content also was stable in the skins of grapes and pomace taken after fermentation and stored for a long period.[44] lH- and 13C-NMR data for the four most common forms of resveratrols are reported in literature.[38]

Biosynthesis

Resveratrol is produced in plants by the action of the enzyme, resveratrol synthase.[45]

Biotransformation

The grapevine fungal pathogen Botrytis cinerea is able to oxidise resveratrol into metabolites showing attenuated antifungal activities. Those include the resveratrol dimers restrytisol A, B, and C, resveratrol trans-dehydrodimer, leachinol F, and pallidol.[46] The soil bacterium Bacillus cereus can be used to transform resveratrol into piceid (resveratrol 3-O-beta-D-glucoside).[47]

Occurrences

Plants

Resveratrol is a phytoalexin, a class of compounds produced by many plants when they are infected by pathogens or physically harmed by cutting, crushing, or ultraviolet radiation.[48]

Plants that synthesize resveratrol include knotweeds, pine trees including Scots pine and Eastern white pine, grape vines, peanut plants, cocoa bushes, and Vaccinium shrubs that produce berries, including blueberries, raspberries, mulberries, cranberries, and bilberries.[5][7][48]

Foods

The levels of resveratrol found in food varies considerably, even in the same food from season to season and batch to batch.[5]

Wine and grape juice

Beverage Resveratrol (mg/150 ml)[49]
meanrange
Red wine 0.270 — 2.78
Rosé wine 0.125.00×10−03 — 0.29
White wine 0.040.00 — 0.17
Sparkling wine 9.00×10−038.00×10−03 — 1.00×10−02
Green grape juice 5.08×10−030.00 — 1.00×10−02

In a 2007 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.[50]

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.[50] Champagne and vinegar also contain appreciable levels of resveratrol.[49]

Red wine contains between 0.2 and 5.8 mg/l, depending on the grape variety. White wine has much less because red wine is fermented with the skins, allowing the wine to extract the resveratrol, whereas white wine is fermented after the skin has been removed.[5] The composition of wine is different from that of grapes since the extraction of resveratrol from grapes depends on the duration of the skin contact, and the resveratrol 3-glucosides are in part hydrolysed, yielding both trans- and cis-resveratrol.[5]

Selected foods

Food Serving Total resveratrol (mg)[5]
Peanuts (raw) 1 cup (146 grams) 0.01 – 0.26
Peanut butter 1 cup (258 grams) 0.04 – 0.13
Red grapes 1 cup (160 grams) 0.24 – 1.25
Cocoa powder 1 cup (200 grams) 0.28 – 0.46

Ounce for ounce, peanuts have about 25% as much resveratrol as red wine.[5] Peanuts, especially sprouted peanuts, have a content similar to grapes in a range of 2.3 to 4.5 μg/g before sprouting, and after sprouting, in a range of 11.7 to 25.7 μg/g, depending upon peanut cultivar.[48][49]

Mulberries (especially the skin) are a source of as much as 50 micrograms of resveratrol per gram dry weight.[51]

Dietary supplements

Sales of resveratrol supplements increased in 2006 after studies on non-humans.[52]

Harvard University scientist and professor David Sinclair co-founded Sirtris Pharmaceuticals, the initial product of which was a resveratrol formulation;[53] Sinclair became known for making statements about resveratrol like: “(It's) as close to a miraculous molecule as you can find.... One hundred years from now, people will maybe be taking these molecules on a daily basis to prevent heart disease, stroke, and cancer.”[54] Most of the anti-aging field was more cautious, especially with regard to what else resveratrol might do in the body and its lack of bioavailability.[54][55]

Sinclair and others obtained significant news coverage about resveratrol.[56][57] Sinclair is often quoted and pictured in online ads for resveratrol supplements, many of which implied endorsement of the advertised product even though Sinclair had not endorsed them.[58]

History

The first mention of resveratrol was in a Japanese article in 1939 by Michio Takaoka, who isolated it from Veratrum album, variety grandiflorum, and later, in 1963, from the roots of Japanese knotweed.[48][59][60][61]

Research

A 2011 systematic review of existing resveratrol research demonstrated there was not enough evidence to demonstrate its effect on longevity or human diseases, nor could there be recommendations for intake beyond the amount normally obtained through dietary sources, estimated as being less than 4 mg/day.[8] Much of the research showing positive effects has been done on animals, with insufficient clinical research on humans.[8] Resveratrol research in animals and humans remains active.[62][63]

Cancer

As of 2014, the results of studies on laboratory animals or human clinical trials concerning the effects of resveratrol on cancer are inconsistent,[12] even if massive doses of resveratrol are used.[64]

Neurological studies

Resveratrol is under preliminary research for its potential to limit secondary damage after ischemic stroke or acute brain trauma,[65] and its possible effect on cognition.[18]

Cardiovascular studies

A 2018 meta-analysis found no effect on systolic or diastolic blood pressure; a sub-analysis revealed a 2 mmHg decrease in systolic pressure only from resveratrol doses of 300 mg per day, and only in diabetic people.[17] A 2015 meta-analysis found no effect on systolic or diastolic blood pressure; a sub-analysis found a 11.90 mmHg reduction in systolic blood pressure from resveratrol doses of 150 mg per day.[11]

Diabetes

One 2015 review found little evidence for use of resveratrol to treat diabetes.[66] A 2015 meta-analysis found little evidence for an effect of resveratrol on diabetes biomarkers.[67]

Skin

Despite considerable in vitro and animal research, there is no evidence that resveratrol taken orally or topically has any effect on human skin.[68] Preliminary studies have been conducted on resveratrol to understand its potential as a therapy for melanoma.[69][70]

See also

References

  1. 1 2 Camont L, Cottart CH, Rhayem Y, Nivet-Antoine V, Djelidi R, Collin F, Beaudeux JL, Bonnefont-Rousselot D; Cottart; Rhayem; Nivet-Antoine; Djelidi; Collin; Beaudeux; Bonnefont-Rousselot (February 2009). "Simple spectrophotometric assessment of the trans-/cis-resveratrol ratio in aqueous solutions". Anal. Chim. Acta. 634 (1): 121–8. doi:10.1016/j.aca.2008.12.003. PMID 19154820.
  2. 1 2 Resveratrol MSDS on Fisher Scientific website
  3. 1 2 3 Resveratrol MSDS on www.sigmaaldrich.com
  4. ↑ Bechmann LP, Zahn D, Gieseler RK, Fingas CD, Marquitan G, Jochum C, Gerken G, Friedman SL, Canbay A; Zahn; Gieseler; Fingas; Marquitan; Jochum; Gerken; Friedman; Canbay (June 2009). "Resveratrol amplifies profibrogenic effects of free fatty acids on human hepatic stellate cells". Hepatol. Res. 39 (6): 601–8. doi:10.1111/j.1872-034X.2008.00485.x. PMC 2893585. PMID 19207580.
  5. 1 2 3 4 5 6 7 Higdon J, Drake VJ, Steward WP (2016). "Resveratrol". Micronutrient Information Center. Linus Pauling Institute, Oregon State University, Corvallis, OR.
  6. ↑ Fremont, Lucie (January 2000). "Biological Effects of Resveratrol". Life Sciences. 66 (8): 663–673. doi:10.1016/S0024-3205(99)00410-5. PMID 10680575. Retrieved 6 June 2014.
  7. 1 2 Jasiński M, Jasińska L, Ogrodowczyk M; Jasińska; Ogrodowczyk (August 2013). "Resveratrol in prostate diseases - a short review". Cent European J Urol. 66 (2): 144–9. doi:10.5173/ceju.2013.02.art8. PMC 3936154. PMID 24579014.
  8. 1 2 3 Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, et al. (2011). "What is new for an old molecule? Systematic review and recommendations on the use of resveratrol". PLoS ONE. 6 (6): e19881. Bibcode:2011PLoSO...619881V. doi:10.1371/journal.pone.0019881. PMC 3116821. PMID 21698226.
  9. ↑ Sahebkar A, Serban C, Ursoniu S, Wong ND, Muntner P, Graham IM, Mikhailidis DP, Rizzo M, Rysz J, Sperling LS, Lip GY, Banach M (2015). "Lack of efficacy of resveratrol on C-reactive protein and selected cardiovascular risk factors--Results from a systematic review and meta-analysis of randomized controlled trials". Int. J. Cardiol. 189: 47–55. doi:10.1016/j.ijcard.2015.04.008. PMID 25885871.
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  12. 1 2 Carter LG, D'Orazio JA, Pearson KJ; d'Orazio; Pearson (June 2014). "Resveratrol and cancer: focus on in vivo evidence". Endocr. Relat. Cancer. 21 (3): R209–25. doi:10.1530/ERC-13-0171. PMC 4013237. PMID 24500760.
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  18. 1 2 Ahmed, T; Javed, S; Javed, S; Tariq, A; Šamec, D; Tejada, S; Nabavi, SF; Braidy, N; Nabavi, SM (May 2017). "Resveratrol and Alzheimer's Disease: Mechanistic Insights". Molecular Neurobiology. 54 (4): 2622–2635. doi:10.1007/s12035-016-9839-9. PMID 26993301.
  19. ↑ Baell, J; Walters, MA (25 September 2014). "Chemistry: Chemical con artists foil drug discovery". Nature. 513 (7519): 481–3. Bibcode:2014Natur.513..481B. doi:10.1038/513481a. PMID 25254460.
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  24. ↑ Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K; Bleasdale; Chrunyk; Cunningham; Flynn; Garofalo; Griffith; Griffor; Loulakis; Pabst; Qiu; Stockman; Thanabal; Varghese; Ward; Withka; Ahn (March 2010). "SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1". J. Biol. Chem. 285 (11): 8340–51. doi:10.1074/jbc.M109.088682. PMC 2832984. PMID 20061378.
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  31. 1 2 Ansari KA, Vavia PR, Trotta F, Cavalli R; Vavia; Trotta; Cavalli (March 2011). "Cyclodextrin-based nanosponges for delivery of resveratrol: in vitro characterisation, stability, cytotoxicity and permeation study". AAPS PharmSciTech. 12 (1): 279–86. doi:10.1208/s12249-011-9584-3. PMC 3066340. PMID 21240574.
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  37. ↑ Sharan S, Nagar S; Nagar (2013). "Pulmonary Metabolism of Resveratrol: In Vitro and in Vivo Evidence". Drug Metabolism and Disposition. 41 (5): 1163–9. doi:10.1124/dmd.113.051326. PMC 3629805. PMID 23474649.
  38. 1 2 Mattivi F, Reniero F, Korhammer S; Reniero; Korhammer (1995). "Isolation, characterization, and evolution in red wine vinification of resveratrol monomers". Journal of Agricultural and Food Chemistry. 43 (7): 1820–3. doi:10.1021/jf00055a013.
  39. ↑ Lamuela-Raventos RM, Romero-Perez AI, Waterhouse AL, de la Torre-Boronat MC; Romero-Perez; Waterhouse; de la Torre-Boronat (1995). "Direct HPLC Analysis of cis- and trans-Resveratrol and Piceid Isomers in Spanish Red Vitis vinifera Wines". Journal of Agricultural and Food Chemistry. 43 (2): 281–283. doi:10.1021/jf00050a003.
  40. ↑ Resveratrol Photoisomerization: An Integrative Guided-Inquiry Experiment Elyse Bernard, Philip Britz-McKibbin, Nicholas Gernigon Vol. 84 No. 7 July 2007 Journal of Chemical Education 1159.
  41. ↑ Yang I, Kim E, Kang J, Han H, Sul S, Park SB, Kim SK; Kim; Kang; Han; Sul; Park; Kim (2012). "Photochemical generation of a new, highly fluorescent compound from non-fluorescent resveratrol". Chemical Communications. 48 (32): 3839–41. doi:10.1039/C2CC30940H. PMID 22436889.
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  43. ↑ Pantusa M, Bartucci R, Rizzuti B; Bartucci; Rizzuti (2014). "Stability of trans-resveratrol associated with transport proteins". J Agric Food Chem. 62 (19): 4384–91. doi:10.1021/jf405584a. PMID 24773207.
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