Medical Hypotheses (2002) 59(1), 101–104 ª 2002 Elsevier Science Ltd. All rights reserved. doi: 10.1016/S0306-9877(02)00144-5, available online at http://www.idealibrary.com
Red wine consumption and inhibition of LDL oxidation: what are the important components? Alan Howard,1 Mridula Chopra,2 David I. Thurnham,3 John J. Strain,3 Bianca Fuhrman,4 Michael Aviram4 1
The Howard Foundation, Whitehill House, Granhams Road, Great Shelford, Cambridge CB2 5JY, UK; 2School of Pharmacy and Biomedical Sciences, University of Portsmonth, Portsmonth, PO1 2DT, UK; 3Northern Ireland Centre for Diet and Health (NICHE), University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK; 4The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel
Summary The ‘French Paradox’ has been attributed to the regular drinking of red wine. The beneficial effects of red wine could be related to both the alcohol and antioxidant activities of red wine polyphenols. However, it is not clear whether the alcohol component is important and the results of intervention trials are conflicting. In the present report, we have examined the polyphenol composition of red wines used in the various studies and have suggested a few possible reasons for discrepancies in their effects on lipoprotein oxidation. ª 2002 Elsevier Science Ltd. All rights reserved.
Effects of alcohol component
The ‘French Paradox’, that is, the low incidence of heart disease in spite of high fat intake in southern France, has been attributed to the regular drinking of red wine (1). Such beneficial effects of red wine could be related to both the alcohol and antioxidant activities of red wine polyphenols (2–5). Three major issues need to be addressed with regard to the health benefits of red wine. First, is the alcohol component important? Second, what polyphenols are crucial for the antioxidant effects of red wine? Third, what is the bioavailability of the important polyphenols in red wine and how do dietary components influence bioavailability when wine is consumed with food. In this report, we examine the polyphenol composition of red wines used in several studies (6–10) and suggest reasons for the different effects.
Studies, using wine and alcohol-free red wine extract, point to the fact that, while the alcohol component of the wine may be important for a favorable lipid response, such potential health benefits may be independent of the proposed antioxidant effects of red wine (6–9). In a recent human intervention study (8), we have shown that alcohol-free red wine extract can inhibit LDL oxidation ex vivo. In previous studies, red wine containing higher concentration of polyphenols than white wine was shown to be more effective in inhibiting LDL oxidation (6,7,9,10). Whether the alcohol component of wine can facilitate the absorption of polyphenols from red wine is, however, debatable at present.
Received 2 November 2001 Accepted 13 February 2002 Correspondence to: Dr. Mridula Chopra, School of Pharmacy and Biomedical Sciences, University of Portsmonth, Portsmonth PO1 2DT, UK. Phone: +44 23 9284 3562; fax: +44 23 9284 3565; E-mail: [email protected]
Antioxidant polyphenols of wine Red wine contains a variety of polyphenols derived from the skin of the grape and these include flavonols (quercetin and myricetin), flavanols [catechin and epi(gallo)catechin], gallic acid, condensed tannins (catechin and epicatechin polymers), and polymeric anthocyanins. Variations in the concentration of these constituents among red wines (11) may be responsible for the range of antioxidant potential exhibited by
102 Howard et al.
different red wines. Therefore, there is a need to identify the biologically active antioxidant components of red wines. In the table, we compare the composition of two red wines both of which increased the resistance of LDL ex vivo to oxidative modification in human supplementation studies (Table 1) (6,7). Both studies used red wine from Cabernet Sauvignon cultivar; one grown in Israel (7) and the other in France (6). After a similar daily consumption of red wine for two weeks, the inhibitory effect on LDL oxidation was found to be much higher in the Israeli study (7). Comparison of the polyphenol composition of both wines revealed that, though the total polyphenol content of the wines was similar [1650 (Israeli) and 1800 (French) mg/L], the wines differed in their flavonol and monomeric anthocyanin contents (Table 1). In another two studies (8,12), both of which used alcohol-free red wine extracts, only one study (8) showed an increase in the resistance of LDL to oxidation. The comparison of wine composition showed that the concentrations of catechins and anthocyanins were double in the wine which showed an ex vivo inhibitory effect on LDL oxidation (8). Further studies are therefore warranted to confirm the antioxidant effects of individual components of red wine. Also, it is essential that those investigating the antioxidant potential of red wine report the polyphenol content of the wine used for their particular studies. Bioavailability of polyphenols from wine Another important issue, which needs further examination, is the bioavailability of polyphenols from red wine and the effect of various other dietary components on the bioavailability and antioxidant activity of the active constituents. Chemical modification of polyphenols (glycosylation, methylation, or glucuronidation) determines the bioavailability of the active phenolic compounds, as well as their potency to act as antioxidants (13–15). In humans, some polyphenols from red wine were shown to be absorbed and to bind to the LDL particle following red wine ingestion, thus, protecting it from oxidation (6,7). Among the various polyphenols, the bioavailability of anthocyanins (15), quercetin (16), and epicatechin (17) from dietary sources has been reported. However, only data from quercetin are well documented. In plasma, peak concentrations of quercetin have been reported to reach a maximum within an hour of supplementation (16,18). The time at which peak plasma concentrations of quercetin are reached is, however, dependent on its dietary source (18,19). To date, no report has documented the time at which peak plasma concentrations of quercetin are achieved following red wine consumption. Recently, Hollman et al. (20) reported that plasma concentrations of quercetin
Medical Hypotheses (2002) 59(1), 101–104
Table 1 Comparison of LDL lag phase and polyphenol composition of red wine consumed in the Israel and UK study
Polyphenols (mg/L) Total polyphenols
Israel red wine
UK red wine
Flavonols 1. Quercetin 2. Quercetin glycosides 3. Myricetin 4. Myricetin glycosides
5 44 1 19
1 8 1 2
Flavanols 5. Catechin 6. Epicatechin
Phenolics 7. Caftaric acid 8. Caffeic acid 9. Coutaric acid 10. Coumaric acid 11. Gallic acid
11 6 2 11 18
12 5 14 5 35
Stylbenes 12. Resveratrol (trans) 13. Resveratrol (cis)
Monomeric anthocyanins 14. Delphinidin glucoside 15. Cyanidin glucoside 16. Penidin glucoside 17. Petunidin glucoside 18. Malvidin glucoside
<0.1 5 17 <0.1 15
2 <1 2 2 7
Polymeric phenols 19. Procyanidin dimmers 20. Polymeric anthocyanins 21. Tannins Percentage increase in LDL lag phasea
31 27 444
49 22 445
Total polyphenols were determined by the Folin–Ciocalteau method. For HPLC analysis of the individual polyphenols, the method in Ref.  was used and the quantitative results were based on comparison to known standards. Gallic acid and tannins were quantified as gallic acid equivalents, catechin, epicatechin, caftaric acid, and procyanidin dimers were quantified as catechin equivalents, caffeic acid, coutaric acid, coumaric acid, and trans-resveratrol were quantified as caffeic acid equivalents, cis-resveratrol and myricetin glycosides were quantified as trans-resveratrol equivalents, quercetin glycosides, myricetin, quercetin, and delphinidin glucoside were quantified as quercetin equivalents, and cyanidin glucoside, penidin glucoside petunidin glucoside, malvidin glucoside, and polymeric anthocyanins were quantified as malvin equivalents. a Percentage change in the lag phase was calculated following supplementation with red wine for two weeks (6,7).
after the intake of similar amounts of quercetin from red wine were lower than those from onions and not different from those after the consumption of tea. Urinary excretion of quercetin from red wine was also between those of tea and onions. The authors suggested that the bioavailability of quercetin from red wine was slightly less than that from onions and only slightly better than that from tea and this might be related to the type of quercetin present in different dietary sources. ª 2002 Elsevier Science Ltd. All rights reserved.
Red wine consumption and inhibition of LDL oxidation 103
Another important aspect to be remembered is that in plasma, LDL has a half-life of 3–4 days, therefore in any intervention trial with wine apparent an immediate effect on LDL oxidation may not be following wine consumption. For example, in a recently published report (21), in spite of an increase in the plasma concentrations of some phenolics and flavanols (catechins, proanthocyanins, and anthocyanins), no effect on LDL oxidation was observed. In contrast, Miyagi et al. (10) were able to demonstrate a decrease in LDL susceptibility to oxidation two hours after red wine consumption. Such an effect can only be possible if antioxidant components of wine were bound to the LDL particle. Whilst research on pure compounds can be helpful, the total spectrum of polyphenols present in red wine may be important. For instance, quercetin and its glycosides are much more soluble in red wine than in water or in ethanol (personal observation, AN Howard). The most likely explanation for this phenomenon is that other types of polyphenols form soluble complexes with the flavonols. Increased solubility might lead to increased absorption and protection of LDL against oxidation. In a recently published study (8), we found that the effect on LDL oxidation exhibited by red wine extract containing 3.5-mg quercetin was not significantly different from that of 30-mg dose of pure quercetin aglycone. It has been reported that only 24% of the aglycone is absorbed from onions. Provided the same is true for pure supplements, one would have expected a greater response in the group supplemented with 30 mg dose than in the red wine extract. The quercetin supplemented group, however, showed only 4% higher inhibition of LDL oxidation than the wine extract group. The plasma concentrations of quercetin were not measured but one can speculate that the absorption of quercetin from pure supplements was lower. The relative absorption and effectiveness of flavonol glycosides and aglycones from the wine extracts and a pure supplement therefore needs further investigation. CONCLUSION The results of any human intervention study with red wine components may be affected by several factors. There is a wide variation in the polyphenol content, especially flavonols, of different red wines throughout the world (22) and the major determinant factor for this is probably the amount of sunlight to which the grapes are exposed during cultivation (23). Thus, the climatic conditions under which grapes are grown could explain the increased content of flavonols in the Israeli red wines compared to the French wine used in UK study.
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The relative solubility and gastrointestinal absorption of wine polyphenols may increase or decrease in the presence of various dietary components and different individuals may respond differently to the supplements. It is important that all these factors are taken into account when reporting and interpreting data from dietary interventions with wine phenolics.
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