Resveratrol for Proper Cardiovascular Function
Grape Expectations:
To Your Health!

    Thanks to the human heart by which we live . . .  
    - Wordsworth, Intimations of Immortality

Will the "real" active ingredient in wine - the one most responsible for the French Paradox - stand up and take a bow? The French Paradox is the fact that the French, who eat relatively high-fat diets, do not die more of heart disease. For sure, we've heard a lot about certain ingredients of wine, including activin and pycnogenol, over the last few years, each one claiming to be the answer. A feud has even broken out over ownership of the name pycnogenol. Grapes of wrath?

A recent article in the British Medical Journal attempted to drive a grape stake into the heart of the paradox.1 The authors argued that the French haven't always eaten as much fat as they do now and that soon their heart disease rate will catch up with those of other countries. Also, they claimed that drinking red wine doesn't make much difference.

Other researchers have countered with new mortality data showing that other southern European countries, including Spain, Italy, and Switzerland, have low cardiovascular disease also.2 Therefore, the interesting question is not why mortality from heart disease is low in France, but why heart disease is less prevalent in southern than northern Europe.

In a commentary on this controversy, Drs. Meir Stampfer and Eric Rimm of Brigham and Women's Hospital and Harvard Medical School write that there have been many research reports on the benefits of wine and other alcoholic beverages on cardiovascular health.3 So it is difficult to discount the effect of wine in a country that has the highest per capita consumption of it in the world.

THE PROBLEM WITH ALCOHOL
Given that the consumption of wine (and other alcoholic beverages) is a double-edged sword - too much can result in other serious problems, such as liver disease - the questions are raised: Aside from the benefits of alcohol, what are the healthful active ingredients in wine (if any), and what is the evidence for their separate use as dietary supplements? Unfortunately, when the hard data are examined, there are few scientific studies that have progressed beyond the lab, so we are left with little more than hypotheses, or another route of examination (see sidebar).

Nutrients Proven Safer and More Effective Than Foods

Although few will admit it, the scientific evidence for foods - the ordinary stuff we eat every day - is weak. Yet that doesn't stop us from attempting to choose the best foods we possibly can to make up our diets. What's the best way to proceed, barring the double-blind, placebo-controlled studies that we take for granted in other areas?

Aside from overblown concerns about contamination - about which the President and FDA wail, "Food safety is part of our citizens' basic contract with the government" - the food should first have a long history of use, and there should be no known toxicity associated with it. Finally, epidemiological data should not conflict, and they should preferably affirm that there are no harmful aspects of the food. Many foods do not pass these tests, especially since most of the natural chemical compounds of which most foods are comprised have never been tested. It is estimated that less than 5% of the composition of most foods has been subject to the kind of scrutiny that vitamins and other established nutrients have undergone.

POLYPHENOLS AND RESVERATROL
Most of the active ingredients in wine are believed to fall into a category of compounds called polyphenols, which tend to be antioxidants. They include resveratrol (pronounced rez-VEER-a-troll), catechin, epicatechin, and a variety of proanthocyanidins. Of these, resveratrol is present mainly in grape skins, while the proanthocyanidins are present in the seeds. Polyphenols are also found in green tea (for which there is much epidemiological data on anticancer benefits4) and other teas, as well as certain fruits and vegetables. While all of these are surmised to be helpful for the heart as well, there are a number of cautions regarding the polyphenols extracted from the seeds. The principal argument is that fruit seeds are the source of mutagens and other toxic substances that have not traditionally been used for food and should not be consumed. Studies have shown that grape-seed extracts can be mutagenic and embryotoxic.5 Moreover, grape-seed extracts, in particular, have been found to potentiate mutagenic activity.6 This has not been found to be true for grape-skin extracts.

RESVERATROL
Of all the active substances in wine, an excellent case can be made for resveratrol, a member of a subgroup of polyphenols known as phytoalexins.7 Resveratrol is an antioxidant that has been found to decrease the "stickiness" of blood platelets and to help blood vessels remain open and flexible.8 It has been identified in more than 70 plant species, including currants and peanuts, and is produced especially during times of environmental stress, such as adverse weather or attack by insects or pathogens. Grapes are a particularly good source, where resveratrol is found in the skins but not the fruit. This is one reason why red wines have more of it - they are made by prolonged contact with the skins, which impart the dark color. Fresh grape skin contains about 50 to 100 micrograms of resveratrol per gram, while red wine concentrations range from 1.5 to 3 milligrams per liter.

CARDIOVASCULAR EFFECTS
A series of laboratory experiments suggest that the consumption of red wine, containing resveratrol, may reduce the incidence of coronary heart disease.9 Other studies have demonstrated that resveratrol is an effective antioxidant.10 It inhibits oxidation of low-density lipoprotein (LDL, the "bad" cholesterol),11 reduces the damage that LDL can do,12 and protects cells from lipid oxidation in general.13 Among resveratrol's virtues is that it's water-soluble as well as fat-soluble.10 This gives it a broader spectrum of action than those of other well-known antioxidants, such as vitamins C and E, which are limited to aqueous or fatty tissues, respectively. Another likely factor in resveratrol's prevention of atherosclerosis is its ability to help reduce platelet aggregation.14

Adding support to the cardiovascular benefits of resveratrol is a report that a traditional Ayurvedic medicine from India, known for its cardiotonic value, is derived from Vitis vinifera L., the species of grape from which the world's great wines are produced.15 When the medicine, darakchasava, was analyzed, it was shown to have high levels of polyphenols such as resveratrol.

ANTICANCER BENEFITS
A recent study has shown that resveratrol may help prevent cancer.7 It was effective during all three phases of the cancer process - initiation, promotion, and progression - through its antioxidant and antimutagenic activities. Resveratrol also demonstrated anti-inflammatory effects and inhibited the activity of enzymes that promote carcinogenesis. Finally, it inhibited the development of pretumorous lesions in mouse mammary glands treated with a carcinogen in culture, and it inhibited tumor formation in mice. No toxic effects were observed. According to the lead researcher of the study group, "Of all the plants we've tested for cancer chemopreventive activity and all the compounds we've seen, this one has the greatest promise."

Resveratrol has also been shown to inhibit an enzyme needed for DNA synthesis in proliferating cells.16 Especially encouraging is a study showing that, despite resveratrol's anticancer potential, it is minimally toxic to blood-forming cells.17

ANTIVIRAL, ANTIHERPES EFFECTS
In another study, resveratrol was found to inhibit the replication of herpes simplex virus types 1 and 2 in a dose-dependent, reversible manner.18 It was found to work by targeting an early event in the virus's replication cycle. This would make it useful if employed during the first hour of cell infection, and for up to six hours thereafter, perhaps nine at the most. In brain tissue, resveratrol was also found to inhibit the reactivation of viruses from infected neurons, as well as to limit viral growth.

RESERVATROL IS STABLE, UNLIKE OTHER POLYPHENOLS
Research on the chemical stability of resveratrol has shown it to be amazingly stable.19 When grape skins or pomace (the pulpy material left after the juice is pressed from the grapes) was stored for long periods of time without protection from temperature and humidity changes, researchers could find little deterioration of the resveratrol. This result was totally unexpected, given that other polyphenols, including the proanthocyanidins (from grape seeds) are unstable under similar conditions.

Also found in wine is quercetin, a well-studied bioflavonoid whose antioxidant properties may be complementary to those of resveratrol.20 Quercetin too is known to reduce atherosclerotic plaque buildup by helping to reduce LDL oxidation and platelet aggregation.21 Yet another safe polyphenol, found in green tea and supported by widespread use and extensive epidemiological research, is epigallocatechin gallate, which is associated with low cancer rates.22 Green tea itself is an acknowledged cancer preventive in Japan.23

The French have an expression, fin-de-siècle, which translates as the "end of a century" (the nineteenth century, as the term is used), a transition period signaling the end of an era. In light of what we know about the French Paradox, perhaps it is time to say vin-de-siècle. The era of skepticism regarding the health benefits of wine is over. Long live polyphenols - especially those derived from skins!


References

  1. Law M, Wald N. Why heart disease mortality is low in France: the time lag explanation. BMJ 1999 May 29;318:1471-6.
  2. Ducimetière P, Lang T, Amouyel P, Arveiler D, Ferrières J, Marrugat J, Sentí M, Glaser JH. Why mortality from heart disease is low in France. BMJ 2000;320:249.
  3. Stampfer M, Rimm E. Commentary: Alcohol and other dietary factors may be important. BMJ 1999 May 29;318:1476-7.
  4. Kuroda Y, Hara Y. Antimutagenic and anticarcinogenic activity of tea polyphenols. Mutat Res 1999 Jan;436(1):69-97.
  5. Grigorashvili GZ, Podorozhanskaia IZ. Embryotoxic effect of a protein concentrate from grape seeds. Gig Sanit 1984 Jan;(1):75-6.
  6. Catterall F, Souquet JM, Cheynier V, de Pascual-Teresa S, Santos-Buelga C, Clifford MN, Ioannides C. Differential modulation of the genotoxicity of food carcinogens by naturally occurring monomeric and dimeric polyphenolics. Environ Mol Mutagen 2000;35(2):86-98.
  7. Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CWW, Fong HHS, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997;10:218-21.
  8. Bertelli AA, Giovanninni L, Bernini W, et al. Antiplatelet activity of cis-resveratrol. Drugs Exp Clin Res 1996;22(2):61-3.
  9. Ray PS, Maulik G, Cordis GA, Bertelli AA, Bertelli A, Das DK. The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Radic Biol Med 1999 Jul;27(1-2):160-9.
  10. Martinez J, Moreno JJ. Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem Pharmacol 2000 Apr 1;59(7):865-70.
  11. Belguendouz L, Fremont L, Gozzelino MT. Interaction of trans-resveratrol with plasma lipoproteins. Biochem Pharmacol 1998 Mar 15;55(6):811-6.
  12. Draczynska-Lusiak B, Doung A, Sun AY. Oxidized lipoproteins may play a role in neuronal cell death in Alzheimer disease. Mol Chem Neuropathol 1998 Feb;33(2):139-48.
  13. Zini R, Morin C, Bertelli A, Bertelli AA, Tillement JP. Effects of resveratrol on the rat brain respiratory chain. Drugs Exp Clin Res 1999;25(2-3):87-97.
  14. Dobrydneva Y, Williams RL, Blackmore PF. Trans-resveratrol inhibits calcium influx in thrombin-stimulated human platelets. Br J Pharmacol 1999 Sep;128(1):149-57.
  15. Paul B, Masih I, Deopujari J, Charpentier C. Occurrence of resveratrol and pterostilbene in age-old darakchasava, an Ayurvedic medicine from India. J Ethnopharmacol 1999 Dec 15;68(1-3):71-6.
  16. Fontecave M, et al. Resveratrol, a remarkable inhibitor of ribonucleotide reductase. FEBS Lett 1998;421:277-9.
  17. Clement MV, et al. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 1998;92:996-1002.
  18. Docherty JJ, Fu MM, Stiffler BS, Limperos RJ, Pokabla CM, DeLucia AL. Resveratrol inhibition of herpes simplex virus replication. Antiviral Res 1999 Oct;43(3):145-55.
  19. Bertelli AA, Gozzini A, Stradi R, Stella S, Bertelli. Stability of resveratrol over time and in the various stages of grape transformation. Drugs Exp Clin Res 1998;24(4):207-11.
  20. Constant J. Alcohol, ischemic heart disease, and the French paradox. Coron Artery Dis 1997 Oct;8(10):645-9.
  21. Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P, Coleman R, Elis A, Aviram M. Reduced progression of atherosclerosis in apolipoprotein E-deficient mice following consumption of red wine, or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation. Arterioscler Thromb Vasc Biol 1997 Nov;17(11):2744-52.
  22. Weisburger JH. Mechanisms of action of antioxidants as exemplified in vegetables, tomatoes and tea. Food Chem Toxicol 1999 Sep-Oct;37(9-10):943-8.
  23. Fujiki H, Suganuma M, Okabe S, Sueoka E, Suga K, Imai K, Nakachi K. A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea - a review. Cancer Detect Prev 2000;24(1):91-9.

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