A number of in vitro studies have reported that wines possess intrinsic antioxidant activity. Maxwell et al. (1994) reported that red wines themselves had about 30fold greater antioxidant activity than normal human serum, and the contribution of various polyphenols to the total antioxidant activity of red wine has been described (Rice-Evans et al., 1996). It was also observed that the total reactive antioxidant potential of red wines was 6 to 10 times higher than white wine (Campos and Lissi, 1996).
Antioxidant properties of wine have also been observed in vivo. For example, in nine healthy subjects who drank 300 mL of red wine, 18 and 11% increases in serum antioxidant capacity was observed after 1 h and 2 h, respectively, but less than the 22 and 29% increases seen at these times in subjects who took 1000 mg ascorbic acid (Whitehead et al., 1995). Lesser increases in serum antioxidant capacity were observed if the subjects drank white wine, or apple, grape, or orange juice. Plasma antioxidant potential also increased about 20% over baseline 2 h or 4 h after normal subjects consumed red wine or ate 1g/kg of black grapes, respectively (Durak et al., 1999), in agreement with the observation that the presence of ethanol enhances absorption of polyphenols (Ozturk et al., 1999). Others observed that drinking red wine with meals or consumption of red wine polyphenols (1 or 2 g/d) increased total plasma antioxidants by 11 to 15%, respectively, in comparison to a 7% increase by vitamin E (Maxwell et al., 1994; Nigdikar et al., 1998; Serafini et al., 1998; Struck et al., 1994). In contrast to other studies, Struck et al. (1994) observed a greater effect when the subjects drank white rather than red wine. In addition, they observed no changes in plasma vitamin E, vitamin C, or beta-carotene, but a 23% reduction from baseline in plasma retinol levels. Although these results suggest that the enhanced antioxidant potential observed after drinking wine is not due to higher concentrations of plasma antioxidant vitamins, it was reported that 73% of the increase in serum antioxidant capacity following consumption of port wine could be attributed to an increase in serum uric acid levels (Day and Stansbie, 1995), a well-recognized antioxidant (Nyyssonen et al., 1997). Caccetta et al. (2000) also observed an increase in serum uric acid levels 1 and 2 h after red wine consumption in 12 healthy males. On the other hand, Cao et al. (1998) observed an 8% increase in serum antioxidant capacity in elderly women who drank 300 ml of red wine, that could not be attributed to an increase in uric acid or vitamin C.
It should be noted that studies that did not observe an effect of red wine on plasma antioxidant status may reflect too low a consumption (Sharpe et al., 1995) or, as in a rat study, may reflect the limited effects polyphenols may exert when a well-balanced diet with more than adequate intake of micronutrients is consumed (Cestaro et al., 1996). Thus, from the above studies it would appear that polyphenols in wine and grapes demonstrate antioxidant activity, but the expression of this activity can depend on a variety of dietary and other health-related factors.
Citing the presumed role of oxidized LDL in the development of atherosclerosis, a large number of studies have evaluated the role of wines, grapes, or select polyphenols on inhibition of LDL oxidation. For example, Ishikawa et al. (1997) observed that catechins could inhibit LDL oxidation in a dose-dependent manner in vitro, and EGCG appeared to be more potent than vitamin E. Generally, studies have shown that wine polyphenols can inhibit oxidative changes of LDL, and red wine appeared more potent than white wine (Caldu et al., 1996; Rifici et al., 1999). In one study, 3.8 and 10 pM polyphenols extracted from red wine and added to LDLs in vitro inhibited its oxidation by 60 and 98%, respectively (Frankel et al., 1993a). Red wine also inhibited cell-mediated LDL oxidation, while white wine and ethanol were not effective (Rifici et al., 1999). Red wine, catechin, or quercetin also produced inhibitory effects on development of aortic atherosclerotic lesions, reduced the susceptibility of LDL to aggregation (Aviram and Fuhrman, 1998), and subsequent atherogenic modification of LDL in atherosclerotic apolipoprotein E-deficient mice (Hayek et al., 1997).
Polyphenols from grape extract also have the ability to inhibit oxidative changes of LDL (Yamakoshi et al., 1999; Lanningham-Foster et al., 1995). However, although red wine and grape juice could inhibit LDL oxidation, in vitro, LDL oxidation was only inhibited in vivo in those who drank wine (Miyagi et al., 1997). Using a copper chloride-induced LDL oxidative system, addition of grape extracts produced a dose-dependent prolongation of the lag time before LDL oxidation (Miyagi et al., 1997). Frankel et al. (1993a,b) further observed that the inhibition of copper-catalyzed LDL oxidation by dilutions of wine could be mimicked by equal concentrations of quercetin, but inhibition by resveratrol was only about one-half that of quercetin or epicatechin (Frankel et al., 1993b).
About eight times more white wine was required to produce a similar effect on LDL oxidation and increase HDL concentrations (Caldu et al., 1996; Rifici et al., 1999). However, if equal concentrations of wine polyphenols extracted from red or white wine were compared, inhibition of LDL oxidation was similar. Comparing dilutions of red or white wine, red grape juice, or beer, LDL oxidation was inhibited in a dose-dependent manner depending on the final polyphenol concentration (Abu-Amsha et al., 1996). These observations suggest that the reported advantage of red wine over white wine in inhibiting LDL oxidation reflects the higher concentrations of polyphenols in red than white wine, rather than red wine polyphenols being more potent than those found in white wine. However, the potencies of the various polyphenols acting alone versus potential additive or synergistic effects of the combinations found in wines have not been fully elucidated in the assay systems examined.
Despite the positive results suggesting that wine polyphenols can inhibit LDL oxidation in vitro, few studies have examined these effects in vivo. Hayek et al. (1997) fed atherosclerotic apolipoprotein-E-deficient mice red wine, quercetin, or catechin in their drinking water for 42 d. They observed that LDLs isolated from these mice were more resistant to oxidation than LDLs isolated from ethanol-fed control mice. In 15 subjects who drank 8 ml/kg of purple grape juice/d for 14 d, LDL oxidation was reduced 34.5% in comparison to controls (Stein et al., 1999). Others have also demonstrated that red wine consumption by healthy volunteers reduced the susceptibility of their LDL to oxidative damage (Lavy et al., 1994; Nigdikar et al., 1998; Seigneur et al., 1990).
The most significant in vivo effects of red wine consumption on inhibiting LDL oxidation was observed in 17 healthy men given 400 mL of red or white wine for 14 d. Plasma collected from red wine drinkers at the end of the study was about 20% less likely to peroxidize than plasma collected at baseline, and LDLs isolated from these subjects were more resistant to oxidation; effects independent of plasma vitamin E or 6-carotene concentrations (Fuhrman et al., 1995). However, this study has come under question because the results obtained far exceeded the clinical benefit obtained previously by dietary or pharmacologic interventions to prevent LDL oxidation (De Rijke et al., 1996). In addition, other studies have reported no significant change in LDL oxidation lag times after acute or subchronic (10-28 d) consumption of red wine despite marked increases in plasma levels of red wine polyphenols (Sharpe et al., 1995; De Rijke et al., 1996; Caccetta et al., 2000).
It should be noted that flavonoids could also accelerate LDL oxidation if they were added to minimally oxidized LDL (Otero et al., 1997). Also, some flavonoids enhanced LDL aggregation (Rankin et al., 1993), and in cholesterol-fed rabbits, resveratrol actually promoted atherosclerotic lesions in the aorta (Wilson et al., 1996). Since atherosclerotic plaque contain high concentrations of copper and iron which may catalyze LDL oxidation (Dubick et al., 1991), the net in vivo effect of polyphenols on LDL oxidation cannot be predicted easily. Therefore, despite the in vitro inhibition of LDL oxidation and the acute rise in serum antioxidant potential following consumption of red wine or grapes in particular, the limited human data do not provide strong evidence that a major in vivo effect of wine polyphenols is inhibition of LDL oxidation. Further work is needed to define whether these results simply reflect insufficient absorption and/or deposition of polyphenols into the target tissues, or whether different results would be obtained if these compounds were given to individuals with preexisting cardiovascular disease.
Wine may also have a positive influence on risk factors of CVD by inhibiting platelet aggregation and prolonging clotting times. Ethanol has long been known to exert an aspirin-like effect on clotting mechanisms (Renaud and De Lorgeril, 1992); however, the concentrations required to inhibit platelet aggregation have generally been high (Drewnoswski et al., 1996, Demrow et al., 1995). In patients with coronary artery disease, those who drank 330 mL of beer per day (~ 1 bottle/d) for 30 d showed evidence of reduced thrombogenic activity compared with patients who did not consume an alcoholic beverage (Gorinstein et al., 1987). However, this study could not determine whether these effects were due to the ethanol, polyphenols in beer, or both.
Both intravenous or intragastric administration of red wine or grape juice, but not white wine, inhibited platelet-mediated thrombus formation acutely in stenosed dog coronary arteries (Demrow et al., 1995). In addition, low concentrations (nM) of quercetin dispersed platelet thrombi that adhered to rabbit aortic endothelium in vitro (Gryglewski et al., 1987). It was shown that platelet aggregation was inhibited about 70% in rats fed ethanol, white wine, or red wine in their drinking water for 2 or 4 months compared with controls (Ruf et al., 1995). However, if the ethanol or wine was withheld for 18 h, platelet aggregation rebounded to greater than control levels in the ethanol- or white wine-fed groups, whereas aggregation was still inhibited in the red wine group.
Studies of the effects of wine on hemostasis in humans have not been as impressive as the animal studies. In 20 healthy men who consumed 400 mL of red or white wine for 14 d, prothrombin time increased but partial thromboplastin time decreased significantly in both groups (Lavy et al., 1994). When collagen was employed as agonist, no significant change in platelet aggregation was observed. Also, no significant effects on platelet aggregation were observed in 20 hypercholesterolemic subjects who drank red or white wine for 28 d (Struck et al., 1994). In contrast, collagen-induced platelet aggregation was lower in male volunteers who consumed 30 g of ethanol/d (about 2-3 drinks) in the form of red wine or ethanol-spiked clear fruit juice for 28 d when compared to subjects who drank dealcoholized red wine (Pellegrini et al., 1996). However, no difference in platelet aggregation was observed if ADP was employed as agonist. These data prompted the authors to conclude that their observations were due to ethanol and not to components in red wine. On the other hand, Seigneur et al. (1990) reported that ADP-induced platelet aggregation was inhibited following wine consumption. Epinephrine or arachidonic acid-induced platelet aggregation were not affected in these subjects, nor was aggregation affected in subjects who drank white wine or an ethanol solution.
In a comprehensive study by Pace-Asciak et al. (1996), 24 healthy males consumed 375 mL/d of red or white wine, or grape juice without or with added trans-resveratrol (4 mg/L) with meals for 28 d. Only white wine inhibited ADP-induced platelet aggregation, whereas red and white wine and resveratrol-supplemented grape juice inhibited thrombin-induced platelet aggregation. These authors observed that in vitro ADP- and thrombin-induced platelet aggregation was inhibited about 50% by grape juice without or with resveratrol, while red wine nearly abolished platelet aggregation, and white wine had no appreciable effect (Pace-Asciak et al., 1996). In a previous in vitro study these authors reported that platelet aggregation could be inhibited by dealcoholized red wine, quercetin, and resveratrol in a dose-dependent manner (Pace-Asciak et al., 1995).
Most recently, in 10 healthy subjects drinking 5-7.5 ml/kg/d of grape juice for 1 wk, whole blood platelet aggregation was reduced 77% when collagen was used as agonist (Keevil et al., 2000). However, consuming 1 g/d of quercetin supplements did not affect collagen-induced platelet aggregation in healthy men and women (Conquer et al., 1998). Again, these data suggest that the in vitro effects of wine and its polyphenols on platelet aggregation are more pronounced than the in vivo effects in humans. Nevertheless, it remains to be determined whether these effects on platelet aggregation are of clinical importance and can translate into reduced risk from thrombi formation and the risk of a coronary event.
Nitric oxide (NO) is a major mediator of vascular relaxation that also inhibits platelet adherence to endothelium. Evidence suggests that wine polyphenols may modulate the production of nitric oxide, since wines, grape juice, and extracts from grape skins relaxed precontracted rat aortic rings (Andriambeloson et al., 1997; 1998). In addition, quercetin could reproduce the effects of wine and grape fractions, while resveratrol, catechin, and malvidin could not (Fitzpatrick et al., 1995; Keaney, 1995). In human subjects who consumed grape juice for 14 d, endothelial-dependent vasodilation was about three-fold higher than in controls (Stein et al., 1999). Taken together these results are interesting, but most of the work has been in vitro and further studies are needed to define the role of polyphenols in inducing vasodilation, particularly after in vivo consumption, and it remains unknown whether such effects could translate into reduced risk for CVD.
In addition, both red and white wine contain significant amounts of salicylic acid and its dihydroxybenzoic acid metabolites, which also have vasodilator and anti-inflammatory activities (Muller and Fugelsang, 1994). The concentrations of these compounds in wine range from 11-28.5 mg/L, with the concentrations being higher in red than white wine. Again, it remains to be determined whether these compounds are absorbed after drinking wine or whether plasma concentrations attained would have the physiologic effect observed in vitro.
Before consumption of polyphenols as a supplement or in wine can be recommended as part of a dietary regimen to reduce risk factors associated with CVD, it is important to review any evidence related to adverse effects. Generally, consumption of polyphenols through a variety of foods is not likely to produce adverse effects, because of the diversity and varying quantities of polyphenols in plant sources. However, evidence suggests that flavonoids may cross the placenta and become concentrated in the developing fetus and perhaps increase the risk of developing infantile leukemia. Therefore, consumption of large doses of polyphenols probably should be avoided during pregnancy, but this area has received little attention. In addition, chronic pharmacologic doses have been reported to produce adverse effects. For example, doses of 1-1.5 g/d of cianidanol, a flavonoid drug, produced renal failure, hepatitis, fever, hemolytic anemia, thrombocytopenia, and skin disorders (Jaeger et al., 1988). Also, high doses of flavonoids can induce mutagenic effects, produce free radicals, and inhibit enzymes involved in hormone metabolism (Skibola and Smith,
2000). Considering that polyphenols are redox chemicals, these activities may also be due to the concomitant production of hydrogen peroxide by phenolics during their autoxidation in a process that is dependent on divalent metal ions, similar to the metal-induced pro-oxidant effect of vitamin C (Stadler et al., 1995; Arizza and Pueyo, 1991).
The potential adverse effects of some individual polyphenols have also been studied. For example, in subjects consuming about 1 g/d EGCG supplements, approximately the dose found in people who drink >10 cups of green tea/d, some stomach discomfort was noted that resolved if the tablets were taken after a meal. Some transient sleeplessness was also reported, but could be due to caffeine contamination of the extract. The LD50 in rats is reported to be 5g/kg in males and 3.1 g/kg in females, suggesting that EGCG has relatively low acute toxicity, but may express teratogenicity at concentrations potentially achievable with daily consumption. In addition, sensitivity to EGCG reportedly has induced asthma in workers at a green tea factory (Clydesdale, 1999). Thus, concerns of allergic reactions, much like those reported with herbal teas, may need to be considered in susceptible individuals.
Quercetin also appears to be relatively nontoxic with an LD50 in mice over 100 mg/kg. In a phase I clinical study, nephrotoxicity was not observed until a cumulative dose of 1700 mg/m2 was achieved (Clydesdale, 1999). No evidence of carcino-genicity or teratogenicity with quercetin has been reported, even when fed at dietary levels as high as 10% (Clydesdale, 1999).
A study in Portugal observed a dose-dependent relationship between red wine consumption and incidence of gastric cancer (Falcao et al., 1994). However, it is not known if this observation is related to the ethanol, red wine polyphenols, or their interaction with other risk factors. Free radicals have been identified in red wines and their originating grape source, but have not been detected in white wine (Troup et al., 1994). Flavonoids can also express pro-oxidant effects in the presence of copper (Cao et al., 1997) or NO (Ohshima et al., 1998), and Halliwell (1993) reported that plant phenolics may show an oxidant effect against proteins and DNA. Conditions where phenolic compounds act as pro-oxidants have been described (Decker, 1997; Laughton et al., 1989).
The results from the studies summarized here indicate that the polyphenols present in grapes and wine, among other foods, possess antioxidant activity, and have the potential to modify plasma cholesterol and lipoprotein concentrations, inhibit LDL oxidation, reduce platelet aggregation, and have vasorelaxant effects, i.e., modify certain risk factors associated with the development of atherosclerosis or ischemic heart disease in susceptible individuals. Although these effects have been well demonstrated in vitro, in most cases the in vivo results have been less convincing. These differences may simply reflect low rates of absorption of the active compounds, differences in methodologies employed by the various investigators to detect these effects, the antioxidant status of the subjects, or other factors. In most instances, studies in humans have employed healthy subjects, and it is unknown whether potential benefit would be observed in individuals with varying stages of CVD. It is also realized that wines are complex mixtures and their polyphenol content varies. Even in cases where specific polyphenols are studied, the results have not always been consistent. In studies where red wine is reportedly superior to white wine, the differences most likely merely reflect the higher polyphenol concentrations in red than white wine, rather than differences in the potencies of polyphenols that may be found in both wines.
To date, in studies of increases in antioxidant potential in plasma after wine consumption, the changes have been transient and disappear a few hours after drinking. In the platelet aggregation studies, results have been reported for only 1 or 2 time points after drinking, and aggregation may change in response to one agonist, but not another, making the overall physiologic significance difficult to interpret. Also, it remains to be established whether these results would be sustained after continued consumption, or whether adaptation to these effects would occur.
As mentioned above, polyphenols are also present in a number of common fruits and vegetables (Fero-Luzzi and Serafini, 1995; Bravo, 1998; Hertog et al., 1995). Numerous studies have touted the potential health benefits of consuming diets rich in fruits and vegetables, particularly with regard to cancer prevention. Since it is unclear which of the polyphenols offer the most health-promoting advantage, it would seem premature and inappropriate to recommend drinking wine specifically as a major source of polyphenols in an attempt to raise an individual's plasma antioxidant status as a means to reduce risk of CVD. Even in the case where wine may contain a particular polyphenol such as resveratrol, not generally found in other common foods, the evidence that it possesses any specific protective effects against CVD in vivo, is insufficient. On the other hand, there is sufficient information to suggest that for adults, consuming 1 to 2 glasses of wine with meals would not be harmful, and may be beneficial (Meister, 1999). In considering any recommendation for wine, one must always keep in mind the well-known adverse health effects and consequences of chronic ethanol abuse or the effects and risks of acute inebriation (Zakhari and Gordis, 1999; Dufour and Fe Caces, 1993; Rubin, 1993).
From the forgoing discussion, it would appear that despite a wealth of in vitro studies citing the potential efficacy of grape and wine polyphenols against known risk factors of CVD, much research is required to confirm benefit in vivo. Many of these studies employed high doses of flavonoids, and additional studies could address repeated administration of lower doses and/or identify definitively which polyphenols in wine and grapes may be most important for human health. It is also unknown whether individual polyphenols can act in an additive or synergistic fashion in vivo. Since some polyphenols are mutually exclusive in nature (Rice-Evans et al., 1996), it is not known whether packaging them together in a supplement would be potentially harmful.
In summary, the available data to date indicate that grape and wine polyphenols, as well as the complex beverage, possess biologic activity that may potentially mod ify certain risk factors associated with atherogenesis and CVD. Indeed, these polyphenols have the potential to be an important source of nonnutritive antioxidants in the diet (Prior and Cao, 1999). Epidemiologic studies showing an inverse relationship between flavonoid intake and incidence of CVD suggest that individuals 35 to 65 or 70 years of age may benefit most from these compounds. Unfortunately, the data are slim to suggest convincingly that these substances may offer long-term protection from these diseases. There is also no definitive evidence that wine consumption would be beneficial in trying to overcome the adverse health consequences of smoking or other factors associated with an unhealthy lifestyle. Since the best polyphenols to promote health are not known, it also seems premature to recommend dietary supplements containing individual compounds or complexes at this time, particularly since standard Western diets may contain up to 1 g/d of polyphenols (Scalbert and Williamson, 2000). Also, in view of potential adverse effects of various polyphenols, caution is advised against long term intake of gram doses of individual compounds above normal daily dietary levels, and certainly in pregnant women (Skibola and Smith, 2000). As usual, variety, moderation, and balance should remain the best recommendation when considering the addition of wine or various polyphenols to the diet.
The author thanks Amber Large for assistance in the preparation of the manuscript.
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