The Mechanism Behind Resveratrol’s Health Benefits: How Does The “Magic” Happen?

The health benefits of red wine have been well-studied, with resveratrol being the most commonly studied compound and the one that is often credited the most as being beneficial to human health.  Resveratrol is primarily produced in plants (including grapes) in two forms: the cis- and trans- configuration of 3,5,4’-trihydroxy-stilbene.  In terms of wine, resveratrol is an extremely minor compound, with very low doses actually contained therein.  Also, studies on resveratrol tend to focus only on one or two forms, neglecting the possible many metabolites formed after coming in contact with the human digestive system.

Where many studies examining the health effects of resveratrol tend to “go wrong” is that they do not consider what happens to the resveratrol after it is consumed.  Does the resveratrol stay in its original form?  Or does it metabolize into different compounds?  It is not too often that compounds remain in their un-metabolized original forms once they are consumed, and resveratrol is no different.  After resveratrol is consumed, it converts into glucuronide and sulfate metabolites, which have been observed in tiny amounts in the human circulatory system.

In fact, the most common forms of resveratrol after it has come into contact with the various compounds in the human digestive system are the glucuronic acid and sulfate metabolites of trans-resveratrol, though very little is known about

Figure 1 from Ruotolo et al, 2013.

Figure 1 from Ruotolo et al, 2013.

these compounds.  Becoming familiar with these trans-resveratrol metabolites after ingestion could be very beneficial for the study of health benefits of red wine, as knowing these compounds and their mechanisms of action in the body could lead to improved therapies and an overall understanding of how it all “works”.

In terms of structure, resveratrol is very similar to the structure of estrogen diethylstilbestrol (DES), which is a synthetic estrogen that is notorious for being given to pregnant women from the 1940s to the 1970s resulting in significant birth defects, with many of the children continuing to have significant health problems throughout the remainder of their lives.  Like DES, resveratrol has been shown to interact with estrogen receptors (ER), though more so with ERα than ERβ.  Once resveratrol binds to an ER receptor, it can either act as an antagonist or as an agonist, both mechanisms of which could produce markedly different physiological reactions.  Unlike DES, resveratrol and its derivatives seem to have a positive effect on health, whereas DES has quite the opposite effect.

Structure of diethylstilbestrol (DES) Photo By User:Mysid (Self-made in BKChem, scaled in perl.) [Public domain], via Wikimedia Commons

Structure of diethylstilbestrol (DES)
Photo By User:Mysid (Self-made in BKChem, scaled in perl.) [Public domain], via Wikimedia Commons

Studies have shown that the health benefits of resveratrol and its derivative may very well be a result of their interactions with estrogen receptors, however, what is unclear is exactly which form or forms of the metabolized compound is most important, or even the relative importance of all of the metabolites together.  The study presented today aimed to examine the interactions of resveratrol and its derivatives in the presence of human estrogen receptors; in hopes to gain further understanding of how exactly resveratrol in its various forms interacts on a chemical level in humans.

Very Brief Methods

I won’t bore you with a lot of the details here, but if you have questions regarding specific parts of the methods, just let me know and I’d be happy to elaborate further.

Very briefly, the estrogenic and anti-estrogenic activities of resveratrol and its derivatives were tested using the yeast two-hybrid assay.  Also tested was the concentrations beta-galactosidase activity, relative estrogenic potency, as well as concentrations of each individual resveratrol derivative compound.

Human breast cancer cells (cell line MCF-7), which contain both ERα and ERβ receptors, were treated with either resveratrol or the sulfate derivative of resveratrol at concentrations ranging from 50nM to 50μM, with or without the presence of 1nM of 17β-estradiol (a.k.a. “estradiol” or “E2”, the natural sex hormone).

Results

  • The sulfate derivative of resveratrol (trans-resveratrol-3-O-sulfate) was the only derivative to exhibit anti-estrogenic activity on both ERα and ERβ, though there was a significant preference for the former.
    • Trans-resveratrol-3-O-sulfate showed weak/minor agonist behavior.
  • Resveratrol aglycone was very weak and was a non-ER selective antagonist.
  • The resveratrol derivatives resveratrol-3-O-glucoside and the two glucuronide conjugates did not interact with the estrogen receptors on the human breast cancer cells, thereby they had no effect.
  • In yeast cells, there was very little if any uptake of the derivative resveratrol-4’-O-glucuronide (makes sense considering the glucuronide conjugates were found to not interact with the estrogen receptors), though resveratrol aglycone was taken up by the yeast cells.
  • Inside the cells, trans-resveratrol-3-O-sulfate had a concentration of 60nM, while the concentration of resveratrol aglycone inside the cells was 10x greater.
  • 60nM of trans-resveratrol-3-O-sulfate was enough to reduce estradiol activity by 50%.
  • In human breast cancer cells, trans-resveratrol-3-O-sulfate acted as an estradiol antagonist and reduced estradiol-dependent luciferase expression by 40% at a concentration of 50nM.
  • At 4.9μM, trans-resveratrol-3-O-sulfate exhibited a weak agonist effect in human breast cancer cells.
  • At concentrations greater than 1μM, resveratrol increased estradiol-dependent transcriptional activation in human breast cancer cells.
  • At concentrations lower than 1μM, resveratrol and opposite response and acted more as a weak antagonist against the estradiol response.
    • Depending upon the concentration of resveratrol, it can either be a “super-agonist” or a “partial agonist/antagonist”, thus eliciting different responses depending upon how much resveratrol is present.

Conclusions

There is a lot going on with these results, and they are pretty confusing for sure!  From these results, it seems as though resveratrol and its derivatives may perform different mechanisms of action depending upon the concentration of the compounds present in the system.

How does this relate to real-world situations?

Well, first off, by taking a 30mg pill of resveratrol, it has been shown that concentrations of total resveratrol in the blood are around 0.8μM.  Comparing this to a half bottle of resveratrol-rich red wine which may have up to 7.5mg of trans-resveratrol, with an average of about 2mg, this could result in a trans-resveratrol-3-O-sulfate level in the blood of about

By Hungry Girl (originally posted to Flickr as Glass of wine) [CC-BY-2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons

By Hungry Girl (originally posted to Flickr as Glass of wine) [CC-BY-2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons

50nM (that’s if one person drank the entire half bottle).  In order for this study to see a 50% reduction in estradiol activity, the trans-resveratrol-3-O-sulfate concentration required was 50μM. In essence, the amount of trans-resveratrol-3-O-sulfate required to achieve this reduction in estradiol activity is about 1000 times greater than what is actually present in a half bottle of red wine after ingestion.

If it’s physiologically impossible to drink enough red wine to get the benefit of resveratrol without destroying your liver or otherwise dying, how can drinking red wine provide all these supposed benefits as illustrated with the concept of the “French Paradox”?  The authors of this study mentioned, and I tend to agree, that we are not accounting for any interactions with any other cell type in the wine or the body after consumption.  By itself, resveratrol doesn’t have enough of an effect at the doses that are present in red wine, however, interactions with other compounds may prove to be the key behind red wine’s “magic”.

Though this study did not provide the exact mechanism by which resveratrol and its derivatives provide health benefits for humans, however, the results of this study give a very solid hint.  Resveratrol, particularly its most commonly found derivative after ingestion, trans-resveratrol-3-O-sulfate, is shown in this research to bind to estrogen receptors and have either an antagonistic or agonistic effect depending upon the concentration.  Estradiol and other estrogens have been linked to increasing cell proliferation and rapid cell growth in cancerous tumors, so it is possible that resveratrol effectively competes with the blocks estradiol from latching on to the estrogen receptors, thus protecting the body against rapid tumor growth in cancer.  More studies need to be done to confirm this, particularly studies examining the competition between trans-resveratrol-3-O-sulfate and estradiol, but the theory certainly sounds plausible to me.

One other thing that got me thinking was: “if resveratrol is so structurally similar to DES, a harmful synthetic endocrine disruptor that is linked to a plethora of birth defects and health problems, how could it have such an opposite effect?”.  The synthetic DES, while structurally similar, likely has one or a few very small differences between it and resveratrol that upon ingestion is conjugated into a much more harmful compound, while the natural resveratrol is conjugated into a “helpful” compound.  If this is the case, could learning about the estrogenic activity of resveratrol help us understand the mechanisms of these more harmful synthetic endocrine disruptors?  Additionally, could understanding the estrogen activity and mechanisms of resveratrol help us develop a sort of “antidote” to harmful endocrine disruptors? (See a definition of endocrine disruptors here).

These are certainly loaded questions, and ones that cannot be answered by looking at this study alone.  However, due to

Photo by Flickr user Andreanna Moya Photography

Photo by Flickr user Andreanna Moya Photography

the structural and mechanistic similarities, I believe there might be some substance to using resveratrol, or at least the knowledge of the mechanism behind resveratrol’s health benefits, for developing a way to combat against the harmful effects of synthetically-made endocrine disruptors that are currently wreaking havoc on our environment.

I’d love to hear your thoughts on this topic!  I know there are about a million questions that stem from the results of this study, so please feel free to voice your thoughts!  How else do you see the results of this study being beneficial in terms of future use and future study?  Please feel free to leave any comments you may have!

Source: Ruotolo, R., Calani, L., Fietta, E., Brighenti, F., Crozier, A., Meda, C., Maggi, A., Ottonello, S., and Del Rio, D. 2013. Anti-estrogenic activity of a human resveratrol metabolite. Nutrition, Metabolism & Cardiovascular Diseases. http://dx.doi.org/10.1016/j.numecd.2013.01.002.

8 comments for “The Mechanism Behind Resveratrol’s Health Benefits: How Does The “Magic” Happen?

  1. October 7, 2013 at 1:47 pm

    Fascinating!! As an owner of a winery in Uruguay (Artesana), we always tout our Tannats, Uruguay’s signature varietal, as the healthiest of red wines due to their high levels of procyanidins and resveratrol. My colleague, Dr. Francisco Carrau of Bodega Carrau just sequenced the Tannat genome, only the 2nd grape after Pinot Noir to be sequenced. The study has been all over the world news.

    Here is a link: http://www.sciencedaily.com/releases/2013/09/130902101846.htm

    • Becca
      October 7, 2013 at 1:51 pm

      Hi Leslie! Thank you for your great comments! Thanks, also, for the link to your colleagues work on the sequencing of the Tannat genome. That is really cool!

  2. David
    October 8, 2013 at 1:24 am

    Whenever I read an article like this, I think about what Michael Pollan has written about nutritionism. Perhaps there are other undiscovered compounds in wine or it is the delivery mechanism, as Becca points out, the reservatrol concentrations in your blood are lower if you take it in pill form as opposed to drinking red wine. We just know the end result that drinking red wine in moderation has some health benefits.

  3. October 15, 2013 at 10:07 am

    I found a report on a recent study about resveratrol’s fate after it’s metabolized:
    http://www.wine-searcher.com/m/2013/10/fighting-cancer-with-red-wine-compound

    “A new study conducted at the University of Leicester shows that wine drinkers can still reap the benefits of resveratrol even after it has been turned into resveratrol sulfates. The trigger lies within cells, where enzymes are able to convert the sulfates back to resveratrol again.”

    And the resveratrol generated by the sulfates are utilizable by the body.

    I always like finding new studies that support drinking red wine!

    • Becca
      October 17, 2013 at 9:59 am

      Very cool, Diana! Thank you for adding some great info to the topic at hand! I agree with you about enjoying finding new studies that support drinking red wine, though to be honest, I don’t think a negative or null report would deter me too much anyway ;)

  4. grant
    July 10, 2014 at 10:56 pm

    I work in fragrance. are you saying i should drink half a bottle of wine before every shift? ;)

    just kidding. this stuff fascinates me, though!

    *goes to trader joes*…..

    • Becca
      July 11, 2014 at 12:27 pm

      Shout out to Trader Joe’s!!…..that’s where I go most of the time as well! As far as drinking half a bottle of wine before your shift, I would not recommend this behavior, but who am I to judge?? hehehe.

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