*from Wikipedia.org
Resveratrol is a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi. Resveratrol has also been produced by chemical synthesis[1], and is sold as a nutritional supplement derived primarily from Japanese knotweed. Resveratrol extends the life span of several short-living species of animals; however, this effect have not yet been demonstrated in mammals. In mouse and rat experiments, anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. As of July 2008, most of these results are yet to be confirmed in humans. In the only positive human trial, extremely high doses (3–5g) of resveratrol in a special proprietary formulation have been necessary to significantly lower blood sugar. Resveratrol is found in the skin of red grapes and is a constituent of red wine but apparently not in sufficient amounts to explain the "French paradox" that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats.[2]
Resveratrol 
Other names trans-3,5,4'-Trihydroxystilbene;
3,4',5-Stilbenetriol;
trans-Resveratrol;
(E)-5-(p-Hydroxystyryl)resorcinol Identifiers CAS number [501-36-0] SMILES
Properties Molecular
formula C14H12O3 Molar mass
228.25 Appearance white powder with
slight yellow cast Solubility in water 0.03 g/L Solubility in DMSO 16 g/L Solubility
in ethanol 50
g/L Except where noted otherwise, data
are given for
materials in their standard state
(at 25 °C, 100 kPa)
Physiological effects
The groups of Howitz and Sinclair
reported in 2003 in the journal Nature that resveratrol significantly extends
the lifespan of the yeast
Saccharomyces cerevisiae.[3]
Later studies conducted by Sinclair showed that resveratrol also prolongs the
lifespan of the worm Caenorhabditis elegans and the fruit fly
Drosophila melanogaster.[4]
In 2007 a different group of researchers was able to reproduce the Sinclair's
results with C. elegans[5]
but a third group could not achieve consistent increases in lifespan of Drosophila
or C. elegans.[6]
In 2006, Italian scientists obtained
the first positive result of resveratrol supplementation in a vertebrate. Using
a short-lived fish, Nothobranchius furzeri, with a median life span of
nine weeks, they found that 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 the latter'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 that it is its weak toxic action
that stimulated the defense mechanisms and resulted in the life span extension.[7]
Later the same year, Sinclair reported that resveratrol counteracted the
detrimental effects of a high-fat diet in mice. The high fat diet was
compounded by adding hydrogenated coconut oil to the standard diet; it provided
60% of energy from fat, and the mice on it consumed about 30% more calories
then the mice on standard diet. Both the mice fed the standard diet and the
high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the
mice on the high-fat diet. Gene expression analysis indicated the addition of
resveratrol opposed the alteration of 144 out of 155 gene pathways changed by
the high-fat diet. Insulin and glucose levels in mice on the
high-fat+resveratrol diet were closer to the mice on standard diet than to the
mice on the high-fat diet. However, addition of resveratrol to the high-fat
diet did not change the levels of free fatty acids and cholesterol, which were
much higher than in the mice on standard diet. [8]
In 1997 Jang reported that topical
resveratrol applications prevented the skin cancer development in mice treated
with a carcinogen.[9]
There have since been dozens of studies of the anti-cancer activity of resveratrol
in animal models but no clinical trials in humans.[10][11] [12]
Thus, 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.[11] Resveratrol (1 mg/kg orally) reduced the number and
size of the esophageal tumors in rats treated with a carcinogen.[13] 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.[11]
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 in November 2006. Mice fed
resveratrol for 15 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 SIRT1.
Nicholas Wade's interview-article
with Dr. Auwerx[14] states that the dose was 400 mg/kg of body weight (much
higher than the 22 mg/kg of the Sinclair study). For an 80 kg (176 lb) person,
the 400 mg/kg of body weight amount used in Dr. Auwerx's mouse study would come
to 32,000 mg/day. Compensating for the fact that humans have slower metabolic
rates than mice would change the equivalent human dose to roughly 4571 mg/day.
Again, there is no published evidence anywhere in the scientific literature of
any clinical trial for efficacy in humans. There is limited human safety data
(see above). It is premature to take resveratrol and expect any particular
results. 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 energy more efficiently—indicating that the
same pathway shown in the lab mice works in humans.[15]
The most efficient way of
administering resveratrol in humans appears to be buccal
delivery, that is without swallowing, by direct absorption through the inside
of the mouth. When 1 mg of resveratrol in 50 mL solution was retained in the
mouth for 1 min before swallowing, 37 ng/ml of free resveratrol were measured
in plasma 2 minutes later. This level of unchanged resveratrol in blood can
only be achieved with 250 mg of resveratrol taken in a pill form.[16]
About 70% of the resveratrol dose
given orally as a pill is absorbed; nevertheless, oral bioavailability
of resveratrol is low because it is rapidly metabolized in intestines and liver
into conjugated
forms: glucuronate
and sulfonate.[17]
Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected
in the blood after 25 mg oral dose.[17]
Even when a very large dose of resveratrol (2.5 and 5 g) was given as uncoated
pill, the concentration of resveratrol in blood failed to reach the level
necessary for the systemic cancer prevention.[18]
However, resveratrol given in a a proprietary formulation SRT-501 (3 or 5 g),
developed by Sirtris Pharmaceuticals, reached 5-8 times higher blood levels.
These levels did approach the concentration necessary to exert the effects
shown in animal models and in vitro experiments.[19]
In humans[17]
[18] and rats,[20] [21]
[22]
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.[23]
Walle suggests sulfate conjugates are the primary source of activity[17],
Wang et al suggests the glucuronides,[24]
and Boocock et al also emphasized the need for further study of the effects of
the metabolites including the possibility of deconjugation to free resveratrol
inside cells. Goldberd who studied the pharmacokinetics of resveratrol, catechin and quercetin in
humans concluded that "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 and sulfate
conjugates."[25]
The hypothesis that resveratrol from
wine could have higher bioavailability than resveratrol from a pill,[10][26] has been disproved by experimental data.[27][25] 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.[27] In another study, the pharmacokinetics of resveratrol
(25 mg) did not change whether it was taken with vegetable juice, white vine or
white grape juice. The highest level of unchanged resveratrol in the serum (7-9 ng/mL) was
achieved after 30 minutes, and it completely disappeared from blood after 4
hours.[25] The authors of both studies concluded that the trace
amounts of resveratrol reached in the blood are insufficient to explain the
French paradox. They concluded that the beneficial effects of wine could be
explained by the effects of alcohol[25] or the whole complex of substances it contains.[27]
While the health benefits of
resveratrol seem promising, one study has theorized that it may stimulate the
growth of human breast cancer cells, possibly because of resveratrol's chemical
structure, which is similar to a phytoestrogen.[28][29]
However, other studies have found that resveratrol actually fights breast
cancer.[30][31] Citing the evidence that resveratrol is estrogenic,
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.[32] A small study found that a single dose of up to 5 g of trans-resveratrol
caused no serious adverse effects in healthy volunteers.[33]
The mechanisms of resveratrol's
apparent effects on life extension are not fully understood, but they
appear to mimic several of the biochemical
effects of calorie restriction. A new report indicates
that resveratrol activates SIRT1 and PGC-1a and improve functioning of the mitochondria.[34]
Other research calls into question the theory connecting resveratrol, SIRT1, and calorie restriction.[35][36]
An article in press as of January
2008 discusses resveratrol action in cells. It reports a 14-fold increase in
the action of MnSOD.[37]
MnSOD reduces superoxide to H2O2, but H2O2 is not increased due to other
cellular activity. Superoxide O2- is a byproduct of
respiration in complex 1 and 3 of the electron transport chain. It is "not
highly toxic, [but] can extract an electron from biological membrane and other
cell components, causing free radical chain reactions. Therefore is it essential
for the cell to keep superoxide anions in check."[38]
MnSOD reduces superoxide and thereby confers resistance to mitochondrial
dysfunction, permeability transition, and apoptotic death in various diseases.[39]
It has been implicated in lifespan extension, inhibits cancer (e.g. pancreatic
cancer [40][41]), and provides resistance to reperfusion injury and
irradiation damage [42]
[43]
[44].
These effects have also been observed with resveratrol. Ellen 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 [45]
which stimulates FOXO3a transcriptional activity [46]
and it has been shown to enhance the sirtuin-catalyzed deacetylation (activity)
of FOXO3a. MnSOD is known to be a target of FOXO3a, and MnSOD expression is
strongly induced in cells overexpressing FOXO3a [47].
Resveratrol interferes with all
three stages of carcinogenesis - 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 NF-kB,[48]
inhibition of the cytochrome P450 isoenzyme CYP1A1[49]
(although this may not be relevant to the CYP1A1-mediated bioactivation of the
procarcinogen benzo(a)pyrene[50]),
alterations in androgenic[51] actions and expression and activity of cyclooxygenase
(COX) enzymes. In some lineages of cancer cell
culture, resveratrol has been shown to induce apoptosis,
which means it kills cells and may kill cancer cells.[51][52][53][54][55][56]
Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2.
Resveratrol also possesses antioxidant and anti-angiogenic
properties.[57][58]
Resveratrol was reported effective
against neuronal
cell dysfunction and cell death, and in theory could help against diseases such
as Huntington's disease and Alzheimer's disease.[59][60]
Again, this has not yet been tested in humans for any disease.
Research at the Northeastern Ohio
Universities College of Medicine and Ohio State University indicates that
resveratrol has direct inhibitory action on cardiac fibroblasts and may inhibit
the progression of cardiac
fibrosis.[61]
According to Patrick
Arnold it also significantly
increases natural testosterone production from being both a selective estrogen receptor
modulator[62][63]
and an aromatase inhibitor.[64][65]
In December, 2007, work from Irfan
Rahman's laboratory at the University of Rochester demonstrated that resveratrol
increased intracellular glutathionelevels via Nrf2-dependent upregulation
of gamma-glutamylcysteine ligase in lung epithelial cells, which protected them
against cigarette smoke extract induced oxidative stress. [66]
Chemical
and physical properties
Resveratrol
(3,5,4'-trihydroxystilbene) is a polyphenolic
phytoalexin.
It is a stilbenoid,
a derivate of stilbene,
and is produced in plants with the help of the enzyme stilbene synthase.
It exists as two geometric isomers: cis- (Z) and trans-
(E), with the trans-isomer shown in the top image. The trans-
form can undergo isomerisation to the cis- form when exposed to ultraviolet
irradiation.[67] Trans-resveratrol in the powder form was found
to be stable under "accelerated stability" conditions of 75% humidity
and 40 degrees C in the presence of air.[68] Resveratrol content also stayed stable in the skins of
grapes and pomace
taken after fermentation and stored for a long period.[69]
Resveratrol was originally isolated
by Takaoka from the roots of white
hellebore in 1940, and later, in 1963, from the roots of Japanese
knotweed. However, it attracted wider attention only in 1992, when its
presence in wine was suggested as the explanation for cardioprotective effects
of wine.[10]
In grapes, resveratrol is found
primarily in the skin,[70]
and -— in muscadine grapes —- also in the seeds.[71]
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.[70]
The levels of resveratrol found in
food varies greatly. Red wine contains between 0.2 and 5.8 mg/L,[72]
depending on the grape variety, while white wine has much less — the reason
being that red wine is fermented with the skins, allowing the wine to
absorb the resveratrol, whereas white wine
is fermented after the skin has been removed.[70]
A number of reports have indicated that muscadine
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.[73][74]
However, subsequent studies have found no or little resveratrol in different
varieties of muscadine grapes.[75][76]
Content
in wines and grape juice
|
Beverage |
||
|
Muscadine
Wines |
14.1 - 40 |
2.12 - 6 |
|
Red Wines (Global) |
1.98 - 7.13 |
0.30 - 1.07 |
|
Red Wines (Spanish) |
1.92 - 12.59 |
0.29 - 1.89 |
|
Red grape juice (Spanish) |
1.14 - 8.69 |
0.17 - 1.30 |
|
Rose Wines (Spanish) |
0.43 - 3.52 |
0.06 - 0.53 |
|
Pinot Noir |
0.40 - 2.0 |
0.06 - 0.30 |
|
White Wines (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.[77]
In a review of published resveratrol
concentrations, the average resveratrol concentration in red wines is 1.9 ± 1.7
mg trans-resveratrol/l (8.2 ± 7.5 µM), ranging from non-detectable levels to
14.3 mg/l (62.7 µM) trans-resveratrol. Levels of cis-resveratrol follow the
same trend as trans-resveratrol.[78]
Reports suggest that some aspect of
the wine making process converts piceid to resveratrol in wine, as wine seems to have twice the
average resveratrol concentration of the equivalent commercial juices.[74]
"All of the muscadine table
wines sampled had greater trans and cis resveratrol concentrations than any
other wines sampled. The muscadine table wines varied between 9.2 and 31.9 mg/L
cis-resveratrol and between 4.9 and 13.4 mg/L trans-resveratrol."[74]
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 resveratrol concentrations than any other wine or
region.[78]
|
Food |
Serving |
Total
resveratrol (mg)[79] |
|
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 |
Ounce for ounce, peanuts have about
half the amount of resveratrol as that found in red wine. The average amount of
resveratrol in one ounce of peanuts in the marketplace (about 15 whole) is 79.4
µg/ounce.
In comparison, some red wines
contain approximately 160 µg/fluid ounce.[80]
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 micromol/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.[81]
Blueberries
have about twice as much resveratrol as bilberries,
but there is great regional variation. These fruits have less than ten percent
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. [82]
Resveratrol nutritional supplements, first sourced from
ground dried grape skins and seeds (sometimes from residual byproducts of
winemaking),[citation needed] are now
primarily derived from the cheaper, more concentrated Japanese
knotweed which contains up to 187 mg/kg in the dried root.[citation needed]
As a result of extensive news
coverage,[83][84] sales of supplements greatly increased in 2006,[85][86]
despite cautions that benefits to humans are unproven.[87][86]
There is also concern in the scientific community that many of the
currently-available resveratrol supplements contain little or none of the
active ingredient. [88]
Scientists are also studying three
other synthetic compounds based on resveratrol which more effectively activate
the same biological mechanism.[89]
The compound called SRT 1720 seems
to be 1000 times more effective than resveratrol, although it only increases
SIRT1 activation by 6 times. No data has been publicly produced by Sirtris
regarding this difference in SIRT1 efficiency for the new compound.[90]
A study by Professor Roger Corder
has identified a particular group of polyphenols,
known as oligomeric procyanidins, which they believe offer the greatest
degree of protection to human blood-vessel cells. These are found in greatest
concentration in European red wines from certain areas, which correlates with
longevity in those regions, though a causal effect is still unclear. This new
data may impact the supplement market.[91]
Because they are present in red wine in more significant quantities, they could
offer an alternate explanation of the French
paradox.