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Figure 1. Correlation between wine consumption in eighteen industrialized countries and mortality by coronary heart disease. Adapted from Renaud and de Lorgeril, 1992.

Box 10—3. L'chaim! Healthful Properties of Wine (Continued)

Several recent studies have provided additional epidemiological evidence to support this hypothesis. In the study by Klatsky et al (2003), mortality data of nearly 130,000 California adults who initially had been interviewed between 1978 and 1985 regarding their drinking habits,was obtained through 1998. Compared to groups that either did not drink wine or that drank beer or liquor, wine drinkers had a significantly lower mortality risk.This result was due mostly to the reduced risks of coronary disease and respiratory deaths. Mortality risk reduction did not depend on the type of wine (i.e., red or white) and was consistent for most population subsets (e.g.,men versus women, age, and education). Moreover, the risk of coronary disease decreased as wine drinking frequency increased, from less than once per week to daily or almost daily. Finally, it has also been recently suggested (Pinder and Sandler, 2004) that wine consumption might provide a protective effect against dementia and the onset of Alzheimer's disease.

In another epidemiological study, the mortality of 24,000 Danish adults was followed for nearly thirty years (Gr0nbxk et al., 2000). Although moderate consumption of beer or liquor had little effect on mortality, a significant reduction in mortality risk was associated with wine consumption, even up to twenty-one glasses per week.As for the California study, reduced incidence of heart disease accounted for most of the overall reduction in mortality risks, although reduced cancer risks were also observed. It is important to note that these and other epidemio-logical studies that show positive associations of wine consumption and reduced mortality do not account for other factors that may influence mortality, such as exercise, diet, other health habits, and genetics. Finally, it should be emphasized that heavy wine drinking may increase mortality risk (due, for example, to cirrhosis or automobile accidents).

Effect of wine consumption on heart disease

High rates of coronary heart disease within a population are associated with those groups that consume high saturated fat diets.Yet, in some countries, such as France and Italy, where saturated fat consumption is high, heart disease rates are significantly lower than in other countries where fat consumption is also high.This so-called French Paradox is thought to be due to the high levels of wine consumed in these countries (Renaud and de Lorgeril, 1992).

Given the strong epidemiological evidence showing an inverse relationship between coronary disease and wine consumption, what biochemical mechanisms would account for this finding? Several possibilities have been suggested (da Luz and Coimbra, 2004). First, alcohol consumption, in general, is known to increase the high-density lipoprotein (HDL) cholesterol concentration in blood, a factor known to reduce heart disease risks.Alcohol may also increase fibrinolytic activity and decrease platelet aggregation, which similarly reduce plaque formation. Wine, however, contains specific components (other than alcohol) that may also account for the reduction in cardiovascular disease.Among the compounds thought to be most important are polyphenols and flavonoids (Stoclet et al., 2004).These compounds have antioxidant activity and can scavenge superoxide and other reactive oxygen species.Thus,formation of oxidized low-density lipoprotein (LDL), which is known to be toxic to endothelial cells and impair vasorelaxation, are inhibited. Similarly, the antioxidant activity of wine flavonoids can prevent the reaction of superoxide and nitric oxide (NO).The latter has antithrombotic activity, prevents atherosclerosis, and inhibits platelet adhesion and aggregation, and, therefore, is necessary for normal endothelial function.

Another explanation for the role of wine in reducing coronary disease and endothelium-dependent constriction, in particular, was recently described (Corder et al., 2001).These investigators reported that polyphenols in red wine extracts suppress aortic endothelial synthesis of endothelin-1 (ET-1), a peptide that has vasoconstriction activity and that is intimately involved in development of atherosclerosis.This inhibition of ET-1 synthesis was specific for

Box 10—3. L'chaim! Healthful Properties of Wine (Continued)

red wine, because red grape juice was only 15% as inhibitory and white or rosé wine had less than 5% inhibition.The mechanism by which ET-1 synthesis is suppressed was not due to antioxidant activity, but rather to the specific inhibition of the tyrosine kinase cell signaling machinery involved in the initiation of ET-1 synthesis.

Effect of wine consumption on cancer

Based on epidemiological studies, consumption of alcohol, in the form of beer or spirits, generally increases cancer risk mortality, whereas moderate wine consumption appears to lower risks of some cancers (Bianchini and Vainio, 2003; Gr0nbxk et al., 2000; Klatsky et al.,2003). Several wine polyphenolic compounds, such as quercetin and catechin, have been shown to have inhibitory effects, in vitro, against tumor and cancer cells.Two other compounds found in red wine, resveratrol and acutissimin A, have recently attracted considerable attention as molecules that may have anti-cancer properties.

Resveratrol is a polyphenol that may contribute cardiological benefits (as do other wine phenols), in addition to its protective effects on carcinogenesis. Specifically, resveratrol is thought to interfere with the cell signaling cascades that result in the synthesis of NF-kB and AP-1.The latter are transcription factors that activate expression of genes involved in promotion of cell cycle progression, inflammation, anti-apoptosis, and tumorigenesis.Although the precise mechanisms responsible for the anti-carcinogenic and anti-inflammatory effects of resveratrol are not yet established, it appears that by blocking or modulating NF-kB and AP-1 synthesis, resveratrol down-regulates genes necessary for carcinogenesis.

Another component of red wine that has recently been recognized as having anti-cancer activity is acutissimin A (Quideau et al., 2003).Acutissimin A is a polyphenol with an ellagitannin structure (galloyl units linked to glucose) that was originally isolated from the bark of specific types of oak trees (although not from the oak used to make wine barrels). Its activity as a possible anti-cancer agent is due to its ability to inhibit DNA topoisomerase II, an enzyme involved in growth of cancer cells. In fact, acutissimin A is 250 times more inhibitory to this enzyme (in vitro) than etoposide, a drug used clinically to treat some cancers. Finally, it appears that wine, but not grapes, contains acutissimin A. Rather,the presence of acutissimin A in wine is due to its synthesis, during the aging step, from polyphenolic precursors found in grapes. Evidently, the conditions that exist during the aging of wine (i.e., low pH, ethanol, and mildly aerobic atmosphere) are necessary for the synthesis of acutissimin A.

Despite the mostly positive attention that the wine-health connection receives in the popular press, as well as in the scientific literature-gathering headlines, it would be misleading not to note that there are many detractors. Some investigators have argued that dietary diversity, rather than wine, is responsible for the French Paradox, that statistical biases underestimate coronary deaths in France, and that the risk/benefit ratio does not support wine consumption as a means of promoting cardiovascular health (Bleich et al., 2001; Criqui and Ringel, 1994).

References

Bianchini, F., and H. Vainio, 2003. Wine and resveratol: mechanisms of cancer prevention? Eur. J. Cancer Prev. 12:417-425.

Bleich, S., K. Bleich, S. Kropp, H.-J. Bittermann, D. Degner,W. Sperling, E. Rüther, and J. Kornhuber. 2001. Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the French Paradox?'Alcohol Alcohol. 36:189-192. Corder, R.,J.A. Douthwaite, D.M. Lees, N.Q. Khan,A.C.Viseu dos Santos, E.G.Wood, and M.J. Carrier.

2001. Endothelin-1 synthesis reduced by red wine. Nature 414:863-864. Criqui, M.H., and B.L. Ringel. 1994. Does diet or alcohol explain the French paradox? Lancet 344:1 719-1723.

Box 10—3. L'chaim! Healthful Properties of Wine (Continued)

da Luz, P.L., and S.R. Coimbra. 2004.Wine, alcohol and atherosclerosis: clinical evidences and mechanisms. Braz.J. Med. Biol. Res.37:1275-1295.

Klatsky,A.L., G.D. Friedman, M.A.Armstrong, and H. Kipp. 2003.Wine, liquor, beer, and mortality.Am.J. Epidemiol. 158:585-595.

Kundu,J.K., and Y.-S. Suhr. 2004. Molecular basis of chemoprevention by resveratrol: NF-kB and AP-1 as potential targets. Mut. Res. 555:65-80.

Gr0nbxk,M., U. Becker, D.Johansen,A. Gottschau, P. Schnohr, H.O. Hein, G.Jensen, and T.I.A. S0rensen. 2000. Type of alcohol consumed and mortality from all causes, coronary heart disease, and cancer.Ann. In-tern.Med. 133:411-419.

Quideau, S., M. Jourdes, C. Saucier,Y Glories, P. Pardon, and C. Baudry. 2003. DNA topoisomerase inhibitor acutissimin A and other flavano-ellagitannins in red wine.Angew. Chem. Int. Ed. 42:6012-6014.

Pinder, R.M., and M. Sandler. 2004.Alcohol, wine and mental health: focus on dementia and stroke. J. Psy-chopharmacol. 18:449-456.

Renaud, S., and M. de Lorgeril. 1992.Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339:1523-1526.

Stoclet, J.-C.,T. Chataigneau, M. Ndiaye, M.-O. Oak,J.E. Bedoui, M. Chataigneau, and VB. Schini-Kerth. 2004. Vascular protection by dietary polyphenols. Eur.J. Pharmacol. 500:299-313.

ring and functional groups at carbon 1 or 3 are referred to as nonflavonoids. In contrast, compounds containing two or more phenolic rings connected by pyran ring structures are called flavonoids. Both nonflavonoids and flavonoids can be polymerized to form another important class of phenolic compounds called tannins. Tannins consisting of flavonoid phenols are especially important in wine due to their bitter flavor and color stabilization properties.

Within the flavonoid group are several different types of compounds, including the flavonols, catechins, and anthocyanins. These are extracted from the grape skins and seed just after the grapes have been crushed. In general, the longer the wine is in contact with the seed and skin and the higher the temperature, the more of these substances will be extracted. In the manufacture of red wine, this material is left in contact with the pressed juice for several days, even during fermentation, whereas it is removed almost immediately after crushing for white wine manufacture (see below).Thus, although both red wine and white wine contain phenolic compounds, the concentration in red wines is usually at least four times higher than that of white wine.Importantly, many of these phenolics are responsible for pigmentation of grapes and, subsequently, the color of the wine. Antho-cyanins, for example, have red or blue-red color and make red wines red. Most of the an-thocyanins are attached, via ester linkages, to one or two glucose molecules, which enhances their solubility and stability.

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