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.
Abu-Amsha, R., Croft, K.D., Puddey, I.B., Proudfoot, J.M., and Beilin, L.J. 1996. Phenolic content of various beverages determines the extent of inhibition of human serum and low-density lipoprotein oxidation in vitro: identification and mechanism of action of some cinnamic acid derivatives from red wine, Clin. Sci., 91:449-458. Andriambeloson, E., Kleschyov, A.L., Muller, B., Beretz, A., Stoclet, J.C., and Andriantsitohania, R. 1997. Nitric oxide production and endothelium-dependent vasorelaxation induced by wine polyphenols in rat aorta, Brit. J. Pharmacol., 120:1053-1058. Andriambeloson, E., Magnier, C., Haan-Archipoff, G., Lobstein, A., Anton, R., Beretz, A., Stoclet, J.C., and Andriantsitohaina, R. 1998. Natural dietary polyphenolic compounds cause endothelium-dependent vasorelaxation in rat thoracic aorta, J. Nutr., 128:2324-2333.
Arai, Y., Wantanabe, S., Kimira, M., Shimoi, K., Mochizuki, R., and Kinae, N. 2000. Dietary intake of flavonoids, flavones, and isoflavones by Japanese women and the inverse correlation between Quercetin intake and plasma LDL cholesterol concentration, J. Nutr., 130:2243-2250.
Arizza, R.R. and Pueyo, C. 1991. The involvement of reactive oxygen species in the direct acting mutagencity of wine, Mutat. Res., 251:115-121. Aviram, M. and Fuhrman, B. 1998. Polyphenolic flavonoids inhibit macrophage-mediated oxidation of LDL and attenuate atherogenesis, Atherosclerosis, 13:S45-S50.
Bell, J.R.C., Donovan, J.L., Wong, R., Waterhouse, A.L., German, J.B., Walzem, R.L., and Kasim-Karakas, S.E. 2000. Catechin in human plasma after ingestion of a single serving of reconstituted red wine, Am. J. Clin. Nutr., 71:103-108.
Bravo, L. 1998. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance, Nutr. Rev., 56:317-333.
Brouillard, R., George, F., and Fougerousse, A. 1997. Polyphenols produced during red wine ageing, Biofactors, 6:403-410.
Burkitt, M.J. and Duncan, J. 2000. Effects of trans-resveratrol on copper-dependent hydroxyl-radical formation and DNA damage: evidence for hydroxyl-radical scavenging and a novel, glutathione-sparing mechanism of action, Arch. Biochem. Biophys., 381:253-263.
Burr, M.L. 1999. Explaining the French paradox, J. R. Soc. Health, 115:217-219.
Caccetta, R.A.-A., Croft, K.D., Beilin, L.J., and Puddey, I.B. 2000. Ingestion of red wine significantly increases plasma phenolic acid concentrations but does not acutely affect ex vivo lipoprotein oxidizability, Am. J. Clin. Nutr, 71:67-74.
Caldu, P., Hurtado, I., and Fiol, C. 1996. White wine reduces the susceptibility of low-density lipoprotein to oxidation, Am. J. Clin. Nutr., 63:403.
Campos, A.M. and Lissi, E.A. 1996. Total antioxidant potential of Chilean wines, Nutr. Res., 16:385-389.
Canali, R., Vignolini, F., Nobili, F., and Mengheri, E. 2000. Reduction of oxidative stress and cytokine-induced neutrophil chemoattractant (CINC) expression by red wine polyphenols in zinc deficiency intestinal damage of rat, Free Rad. Biol. Med., 28:1661-1670.
Cao, G., Russell, R.M., Lischner, N., and Prior, R.L. 1998. Serum antioxidant capacity is increased by consumption of strawberries, spinach, red wine or vitamin C in elderly women, J. Nutr., 128:2383-2390.
Cao, G., Sofic, E., and Prior, C. 1997. Antioxidant and pro-oxidant behavior of flavonoids: structure-activity relationships, Free Rad. Biol. Med., 22:749-760.
Cestaro, B., Simonetti, P., Cervato, G., Brusamolino, A., Gatti, P., and Testolin, G. 1996. Red wine effects on peroxidation indexes of rat plasma and erythrocytes, in J. Food. Sci. Nutr., 47:181-189.
Chan, P.T., Fong, W.P., Cheung, Y.L., Huang, Y., Ho, W.K., and Chen, Z.Y. 1999. Jasmine green tea epicatechins are hypolipidemic in hamsters (MesocritcetusAuratus) fed a high-fat diet, J. Nutr., 129:1094-1101.
Chun, Y.J., Kim, M.Y., and Guengerich, F.P. 1999. Resveratrol is a selective human cytochrome P450 1A1 inhibitor, Biochem. Biophys. Res. Commun., 262:20-25.
Cleophas, T.J., Tuinenberg, E., Van Der Meulen, J., and Zwinderman, K.H. 1996. Wine consumption and other dietary variables in males under 60 before and after acute myocardial infarction, Angiology, 47:789-796.
Clifford, A.J., Ebeler, J.D., Bills, N.D., Hinrichs, S.H., Teissedre, P.L., Waterhouse, A.L. 1996. Delayed tumor onset in transgenic mice fed an amino acid-based diet supplement with red wine solids, Am. J. Clin. Nutr, 64:748-756.
Clydesdale, F.M. (ed). 1999. Epigallocatechin and epigallocatechin-3-gallate, Crit. Rev. Food Sci. Nutr., 39:215-226.
Conquer, J.A., Miaani, G., Azzini, E., Raguzzini, A., Holub, B.J. 1998. Supplementation with Quercetin markedly increases plasma Quercetin concentration without effect on selected risk factors for heart disease in healthy subjects, J. Nutr, 128:593-597.
Constant, J. 1997. Alcohol, ischemic heart disease, and the French Paradox, Clin. Cardiol., 20:420-424.
Criqui, M.H. and Ringel, B.L. 1994. Does diet or alcohol explain the French Paradox, Lancet, 34:1719-1723.
Croft, K.D. 1998. The chemistry and biological effects of flavonoids and phenolic acids, Ann. N.Y. Acad. Sci., 854:435-442.
Das, D.K., Sato, M., Ray, P.S., Maulik, G., Engelman, R.M., and Bertelli, A.A. 1999. Cardioprotection of red wine: role of polyphenolic antioxidants, Drugs Exp. Clin. Res., 25:115-120.
Day, A. and Stansbie, D. 1995. Cardioprotective effect of red wine may be by urate, Clin. Chem, 41:1319-1320.
Decker, E.A. 1997. Phenolics: pro-oxidants or antioxidants, Nutr. Rev., 55:396-398.
Demrow, H.S., Slane, P.R., and Folts, J.D. 1995. Administration of wine and grape juice inhibits in vivo patients' activity and thrombosis in stenosed canine arteries, Circulation, 91:1182-1188.
De Rijke, Y.B., Demacker, P., Assen, N.A., Sloots, L.M., Katan, M.B., and Stalenhoef, A.F.H. 1996. Red wine consumption does not effect oxidizabilitiy of low-density lipoproteins in volunteers, Am. J. Clin. Nutr., 63:329-334.
de Vries, J.H.M., Hollman, P.C.H., Meyboom, S., Buysman, M.N.C.P., Zock, P.L., van Staveren, W.A., and Katan, M.B. 1998. Plasma concentrations and urinary excretion of the antioxidant flavonols Quercetin and Kaempferol as biomarkers for dietary intake, Am. J. Clin. Nutr., 68:60-65.
Dresoti, I.E. 1996. Bioactive ingredients: antioxidants and polyphenols in tea, Nut. Rev., 54:S51-S58.
Dresoti, I.E. 2000. Antioxidant polyphenols in tea, cocoa, and wine, Nutr., 16:692-694.
Drewnoswski, A., Henderson, S.A., and Shore, A.B., et al. 1996. Diet quality and dietary diversity in France: implications for the French Paradox, J. Am. Diet Assoc., 96:663-669.
Dubick, M.A., Hunter, G.C., and Keen, C.L. 1991. Trace element and mineral concentrations in serum and aorta from patients with abdominal aneurysmal or occlusive disease, J. Trace Elem. Exp. Med., 4:173-182.
Dubick, M.A. and Omaye, S.T. 2001. Modification of atherogensis and heart disease by grape wine and tea polyphenols, in Handbook of Nutraceuticals and Functional Foods (Wildman REC, ed.), CRC Press, Boca Raton, FL, pp. 235-260.
Dufour, M.C. and Fe Caces, M. 1993. Epidemiology of the medical consequences of alcohol, Alcohol Health Res. Wld., 17:265-271.
Durak, I., Koseoglu, M.H., Kacmaz, M., Buyukkocak, S., Cimen, B., and Ozturk, H.S. 1999. Black grape enhances plasma antioxidant potential, Nutr. Res., 19:973-977.
Falcao, J.M., Dias, J.A., Miranda, A.C., Leitao, C.N., Lacerda, M.M., and da Motta, L.C. 1994. Red wine consumption and gastric cancer in Portugal: a case-control study, Eur. J. Cancer Prev., 3:269-276.
Fero-Luzzi, A. and Serafini, M. 1995. Polyphenols in our diet: do they matter, Nutrition, 11:399-400.
Fitzpatrick, D.F., Hirschfield, S.L., and Coffey, R.G. 1995. Endothelium-dependent vasore-laxing activity of wine and other grape products, Am. J. Physiol., 265:H774-H778.
Frankel, E.N., Kanner, J., German, J.B., Parks, E., and Kinsella, J.E. 1993a. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine, Lancet, 341:454-457.
Frankel, E.N., Waterhouse, A.L., and Kinsella, J.E. 1993b. Inhibition of human LDL oxidation by resveratrol, Lancet, 341:1103-1104.
Frankel, E.N., Waterhouse, A.L., and Teissedre, P.L. 1995. Principal phenolic phytochemicals in selected California wines and their antioxidant activity in inhibiting oxidation of human low-density lipoproteins, J. Agric. Food Chem., 43:890-894.
Fuhrman, B., Lavy, A., and Aviram, M. 1995. Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation, Am. J. Clin. Nutr., 61:549-554.
Goldberg, D.M. 1995. Does wine work? Clin. Chem., 41:14-16.
Goldberg, D.M., Garovic-Kocic, V., Diamandis, E.P., and Pace-Asciak, C.R. 1996. Wine: does color count? Clin. Chim. Acta, 246:183-193.
Gorinstein, S., Zemser, M., Lichman, I., Berebi, A., Kleipfish, A., Libman, I., Trakhtenberg, S., and Caspi, A. 1987. Moderate beer consumption and the blood coagulation in patients with coronary artery disease, J. Intern. Med, 241:47-51.
Gryglewski, R.J., Korbut, R., Robak, J., and Swies, J. 1987. On the mechanism of antithrombotic action of flavonoids, Biochem. Pharm., 36:317-322.
Gugler, R., Leschik, M., and Dengler, H.L. 1975. Disposition of quercetin in man after single oral and intravenous doses, Eur. J. Clin. Pharmacol., 9:229-234.
Halliwell, B. 1993. Antioxidants in wine, Lancet, 341:1538.
Hayek, T., Fuhrman, B., Vaya, J., Roenblat, M., Belinky, P., Coleman, R., Elis, A., and Aviram, M. 1997. 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., 17:2744-2752.
Hegsted, M.D. and Ausman, L.M. 1988. Diet, alcohol and coronary heart disease in Men, J. Nutr., 118:1184-1189.
Hein, H.O., Suadicani, P., Gyntelbery, F. 1997. Alcohol consumption, S-LDL-cholesterol and risk of heart disease. 6-year follow-up in the Copenhagen male study, Ugeskritt Laeger, 159:4110-4416.
Hertog, M.G.L., Feskens, E.J.M., Hollman, P.C.H., Katan, M.B., and Kromhout, D. 1993a. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen elderly study, Lancet, 342:1007-1011.
Hertog, M.G.L., Feskens, E.J.M., Kromhout, D. 1997. Antioxidant flavonols and coronary heart disease risk, Lancet, 349:699.
Hertog, M.G., Hollman, P.C., Katan, M.B., and Kromhout, D. 1993b. Intake of potentially anticarcinogenic flavonoids and their determinants in adults in the Netherlands, Nutr. Cancer, 20:21-29.
Hertog, M.G.L., Kromhout, K., Aravanis, C., Blackburn, H., Buzina, R., Fidanza, F., Giampaolis, S., Jansen, A., Menotti, A.L., Nedeljkovic, S., Pekkarinen, M., Simic, B.O., Toshima, H., Feskens, E.J.M., Hollman, P.C.H., and Katan, M.B. 1995. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study, Arch. Int. Med., 155:381-386.
Hollman, P.C.H., Feskens, E.M.J., and Katan, M.B. 1999. Tea flavonols in cardiovascular disease and cancer epidemiology, Proc. Soc. Exp. Biol. Med, 220:198-202.
Hollman, P.C.H., Van der Gaag, M., and Mengelers, M.J.B. 1996. Absorption and disposition kinetics of the dietary antioxidant quercetin in man, Free Rad. Biol. Med., 21:703-707.
Hung, L.-M., Chen, J.-K., Huang, S.-S., Lee, R.-S., Su, M.-J. 2000. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes, Cardiovascular Res., 47:549-555.
Ishikawa, T., Suzukawa, M., Ito, T., Yoshida, H., Ayaori, M., Nishiwaki, M., Yonemura, A., Hara, Y., and Nakamura, H. 1997. Effect of tea flavonoid supplementation on the susceptibility of low-density lipoprotein to oxidative modification, Am. J. Clin. Nutr., 66:261-266.
Jaeger, A., Walti, M. and Neftel, K. 1988. Side effects of flavonoids in medical practice, Prog. Clin. Biol. Res, 280:379-394.
Keaney, J.F., Jr. 1995. Atherosclerosis, oxidative stress, and antioxidant protection in endothe-lium-derived relaxing factor action, Prog. Cardiovasc. Dis., 38:129-154.
Keevil, J.G., Osman, H.E., Reed, J.D., Folts, J.D. 2000. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation, J. Nutr., 130:53-56.
King, A. and Young, G. 1999. Characteristics and occurrences of phenolic phytochemicals, J. Am. Diet Assoc., 99:213-218.
Klatsky, A.L., Armstrong, M.A., and Friedman, G.D. 1997. Red wine, white wine, liquor, beer and risk for coronary artery disease hospitalization, Am. J. Cardiol., 80:416-420.
Klurfeld, D.M. and Kritchevsky, D. 1981. Differential effect of alcoholic beverages on experimental atherosclerosis in rabbits, Exp. Mol. Pathol., 34:62-71.
Knekt, P., Jarvinen, R., Reunanen, A. and Maatela, J. 1996. Flavonoid intake and coronary mortality in Finland: a cohort story, BMJ, 312:478-481.
Lanningham-Foster, L., Chen, C., Chance, D.S., and Loo, G. 1995. Grape extract inhibits lipid peroxidation of human low density lipoprotein, Biol. Phar. Bull., 18:1347-1351.
Laughton, M.L., Halliwell, B., Evans, P., Robin, J., and Hoult, S. 1989. Antioxidant and prooxidant actions of the plant phenolics quercetin, gossypol and myricetin. Effects on lipid peroxidation, hydroxyl radical generation and bleomycin-dependent damage to DNA, Biochem. Pharmacol., 38:2859-2865.
Lavy, A., Fuhrman, B., Markel, A., Dankner, G., Amotz, A.B., Presser, D., and Aviram, M. 1994. Effect of dietary supplementation of red or white wine on human blood chemistry, hematology and coagulation: favorable effect of red wine on plasma high-density lipoprotein, Ann. Nutr. Metab., 38:287-294.
Law, M. and Wald, N. 1999. Why heart disease mortality is low in France: the time lag explanation, BMJ, 318:1471-1480.
Maiani, G., Serafini, M., Salucci, M., Axxini, E., Ferro-Luzzi, A. 1997. Application of new high-performance liquid chromatographic method for measuring selected polyphenols in human plasma, J. Chromat. B. Biomed. Sci. Appl., 692:311-317.
Manach, C., Morand, C., Texier, O., Agullo, G.A., Demigne, C., and Ramsey, C. 1996. Bioavailability, metabolism, and physiological impact of 4-oxo-flavonoids, Nutr. Res., 16:517-544.
Manach, C., Morand, C., Texier, O., Favier, M.L., Agullo, G., Demigne, C., Regerat, F., and Remesy, C. 1995. Quercetin metabolites in plasma of rats fed diets containing rutin or quercetin, J. Nutr., 125:1911-1922.
Manach, C., Texier, O., Morand, C., Crespy, V., Francoise R., Demigne, C., and Remesy, C. 1999. Comparison of the bioavailability of quercetin and catechin in rats, Free Rad. Biol. Med., 27:1259-1266.
Maxwell, S., Cruickshank, A., and Thorpe, G. 1994. Red wine and antioxidant activity in serum, Lancet, 344:193-194.
Meister, K. 1999. Moderate Alcohol Consumption and Health, American Council on Science and Health Report, New York.
Miyagi, Y., Miwa, K., and Inoue, H. 1997. Inhibition of human low-density lipoprotein oxidation by flavonoids in red wine and grape juice, Am. J. Cardiol., 80:1627-1631.
Muller, C.J. and Fugelsang, K.C. 1994. Take two glasses of wine and see me in the morning, Lancet, 334:1428-1429.
Muller, C.J. and Fugelsang, K.C. 1997. Red wine but not white: the importance of fully characterizing wines used in health studies, Am. J. Clin. Nutr., 66:447-51.
Nigdikar, S.V., Williams, N.R., Griffin, B.A., and Howard, A.N. 1998. Consumption of red wine polyphenols reduces the susceptibility of low-density lipoproteins to oxidation in vivo, Am. J. Clin. Nutr., 68:258-265.
Nyyssonen, K., Porkkala-Sarataho, E., and Salonen, J.T. 1997. Ascorbate and urate are the oxidation in Finnish men, Atherosclerosis, 130:223-233.
Ohshima, H., Yoshie, Y., Auriol, S., and Gilibert, I. 1998. Antioxidant and pro-oxidant actions of flavonoids: effects on DNA damage induced by nitric oxide, peroxynitrite and nitroxyl anion, Free Rad. Biol. Med., 25:1057-1065.
Otero, P., Viana, M., Herrera, E., and Bonet, B. 1997. Antioxidant and prooxidant effects of ascorbic acid, dehydroascorbic acid and flavonoids on LDL submitted to different degrees of oxidation, Free Rad. Res., 27:619-626.
Ozturk, H.S., Kacmaz, M., Cimen, M.Y.B., and Durak, I. 1999. Red wine and black grape strengthen blood antioxidant potential, Nutr., 15:954.
Pace-Asciak, C.R., Hahn, S., Diamandis, E.P., Soleas, G., and Goldberg, D.M. 1995. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease, Clin. Chim. Acta, 235:207-219.
Pace-Asciak, C.R., Rounova, O., Hahn, S.E., Diamandis, E.P., and Goldberg, D.M. 1996. Wines and grape juices as modulators of platelet aggregation in healthy human subjects, Clin. Chim. Acta, 246:163-182.
Pellegrini, N., Pareti, F.I., Stabile, F., Brusamolino, A., Simonetti, P. 1996. Effects of moderate consumption of red wine on platelet aggregation and haemostatic variables in healthy volunteers, Eur. J. Clin. Nutr., 50:209-213.
Prior, R.L., Cao, G. 1999. Antioxdiant capacity and polyphenolic components of teas: implications for altering in vivo antioxidants status, Proc. Soc. Exp. Biol. Med., 220:255-261.
Rankin, S.M., de Whalley, C.V., Hoult, J.R., Jessup, W., Wilkins, G.M., Collard, J., and Leake, D.S. 1993. The modification of low density lipoprotein by the flavonoids myricetin and gossypetin, Biochem. Pharm., 45:67-75.
Renaud, S., De Lorgeril, M. 1992. Wine, alcohol, platelets, and the French Paradox for coronary heart disease, Lancet, 339:1523-1526.
Renaud, S. and Ruf, J.C. 1994. The French Paradox: vegetables or wine, Circulation, 90:3118.
Rice-Evans, C.A., Miller, N.J., and Paganaga, G. 1996. Structure-antioxidant activity relationships of flavonoids and phenolic acids, Free Rad. Biol. Med., 20:933-956.
Rifici, V.A., Stephan, E.M., Schneider, S.H., and Khachadurian, A.K. 1999. Red wine inhibits the cell-mediated oxidation of LDL and HDL, J. Am. Coll. Nutr., 18:137-143.
Rimm, E.B., Katan, M.B., Ascherio, A., Stampfer, M.J., and Willett, W.C. 1996. Relation between intake of flavonoids and risk of coronary heart disease in male health professionals, Ann. Int. Med., 125:384-389.
Rubin, E. 1993. The chemical pathogenesis of alcohol-induced tissue injury, Alcohol Health Res. Wld., 17:272-278.
Ruf, J.C., Berger, J.L., and Renaud, S. 1995. Platelet rebound effect of alcohol withdrawal and wine drinking in rats, Arterioscler. Thromb. Vasc. Biol., 15:140-144.
St. Leger, A.S., Cochrane, A.L., and Moore, F. 1979. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine, Lancet, 1017-1020.
Salah, N., Miller, N.J., Paganaga, G., Tijburg, L., Bolwell, G.P., and Rice-Evans, C. 1995. Polyphenolic flavanols as scavengers of aqueous phase radicals and as chain-breaking antioxidants, Arch. Biochem. Biophys., 322:339-349.
Sato, M., Maulik, G., Ray, P.S., Bagchi, D., Das, D.K. 1999. Cardioprotective effects of grape seed proanthocyanidin against ischemic reperfusion injury, J. Mol. Cell. Cardiol., 31:1289-1297.
Sato, M., Ray, P.S., Maulik, G., Maulik, N., Engelman, R.M., Bertelli, A.E., Bertelli, A., and Das, D.K. 2000. Myocardial protection with red wine extract, J. Cardio. Pharm., 35:263-268.
Scalbert, A. and Williamson, G. 2000. Dietary intake and bioavailability of polyphenols, J. Nutr., 130:2073S-2085S.
Schneider, J., Kaffarnik, H., and Steinmetz, A. 1996. Alcohol, lipid metabolism and coronary heart disease, Herz, 21:217-226.
Seigneur, M., Bonnet, J., Dorian, B., Benchimol, D., Drouiller, F., Gouverneur, G., Larrue, J., Crockett, R., Boisseau, M.R., Ribereau-Gayon, P., and Bricaud, H. 1990. Effect of the consumption of alcohol, white wine, and red wine on platelet function and serum lipid, J. Appl. Cardiol., 5:215-222.
Serafini, M., Maiani, G., and Ferro-Luzzi, A. 1998. Alcohol-free red wine enhances plasma antioxidant capacity in humans, J. Nutr., 128:1003-1007.
Sharp, D. 1993. When wine is red, Lancet, 341:27-28.
Sharpe, P.C., McGrath, L.T., McClean, E., Young, I.S., and Archbold, G.P.R. 1995. Effect of red wine consumption on lipoprotein (a) and other risk factors for atherosclerosis, Q. J. Med., 88:101-108.
Skibola, C.F. and Smith, M.T. 2000. Potential health impacts of excessive flavonoid intake, FreeRad. Biol. Med., 29:375-383.
Soleas, G.J. and Goldberg, D.M. 1999. Analysis of antioxidant wine polyphenols by gas chro-matography-mass spectrometry, Mthd. Enzymol., 299:137-151.
Stadler, R.H., Markovic, J., and Turesky, R.J. 1995. In vitro anti- and pro-oxidative effects of natural polyphenols, Biol. Trace Element Res., 47:299-305.
Stein, J.H., Keevil, J.G., Wiebe, D.A., Aeschilmann, S., and Folts, J.D. 1999. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease, Circ., 100:1050-1055.
Struck, M., Watkins, T., Tomeo, A., Halley, J., and Bierenbaum, M. 1994. Effects of red and white wine on serum lipids, platelet aggregation, oxidation products and antioxidants: a preliminary report, Nutr. Rev., 14:1811-1819.
Sugihara, N., Arakawa, T., Ohnishi, M., and Furuno, K. 1999. Anti- and pro-oxidative effects of flavonoids on metal-induced lipid hydroperoxide-dependent lipid peroxidation in cultured hepatocytes loaded with a-linolenic acid, Free Rad. Biol. Med., 27:1313-1323.
Troup, C.J., Hutton, D.R., Hewitt, D.G., and Hunter, C.R. 1994. Free radicals in red wine, but not in white? Free Rad. Res., 20:63-68.
Ueno, I., Nakano, N., and Hirono, I. 1983. Metabolic fate of [14C] quercetin in the ACI rat, Jpn. J. Exp. Med., 53:41-50.
Ursini, F., Tubaro, F., Rong, J., and Sevanian, A. 1999. Optimization of nutrition: polyphenols and vascular protection, Nutr. Rev., 57:241-249.
van het Hof, L.H., Kivits, G.A.A., Westtrate, J.A., and Tijburg, L.B.M. 1998. Bioavailability of catechins from tea: the effect of milk, Eur. J. Clin. Nutr, 52:356-359.
Whitehead, T.P., Robinson, D., Allaway, S., Syms, J., and Hale, A. 1995. Effect of red wine ingestion on the antioxidant capacity of serum, Clin. Chem., 41:32-35.
Wilson, T., Knight, T.J., Beitz, D.C., Lewis, D.S., and Engen, R.L. 1996. Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits, Life Sciences, 59:15-21.
Xu, R., Yokoyama, W.H., Irving, D., Rein, D., Walzem, R.L., and German, J.B. 1998. Effect of dietary catechin and vitamin E on aortic fatty streak accumulation in hypercholes-terolemic hamsters, Atherosclerosis, 137:29-36.
Yamakoshi, J., Kataoka, S., Koga, T., and Ariga, T. 1999. Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits, Atherosclerosis, 142:139-149.
Zakhari, S. and Gordis, E. 1999. Moderate drinking and cardiovascular health, Proc. Assoc. Am. Phys., 111:148-158.
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