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Published as doi: 10.1096/fj.07-9041com.
 (The FASEB Journal. 2008;22:41-46.)
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(The FASEB Journal. 2008;22:41-46.)
© 2008 FASEB

A novel function of red wine polyphenols in humans: prevention of absorption of cytotoxic lipid peroxidation products

Shlomit Gorelik*, Moshe Ligumsky{dagger}, Ron Kohen* and Joseph Kanner{ddagger},1

* Department of Pharmaceutics, David R. Bloom Center of Pharmacy, School of Pharmacy, the Hebrew University of Jerusalem, Jerusalem, Israel;

{dagger} Gastrointestinal Unit, Division of Internal Medicine, Hadassah Medical Center, Jerusalem, Israel; and

{ddagger} Department of Food Science, ARO, the Volcani Center, Bet Dagan, Israel

1Correspondence: Department of Food Science, ARO, the Volcani Center, Bet Dagan 50250, Israel. E-mail: vtkanner{at}agri.gov.il


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Current evidence supports a contribution of polyphenols to the prevention of cardiovascular disease, but their mechanisms of action are not understood. We investigated the impact of red wine polyphenols on postprandial cytotoxic lipid peroxidation products (MDA) levels in humans. In a randomized, crossover study, the effect of red wine polyphenols on postprandial levels of plasma and urine MDA was investigated. Three meals of 250 g turkey cutlets supplemented by water (A); soaked in red wine after heating plus 200 ml of red wine (B); or soaked in red wine prior to heating plus 200 ml of red wine (C) were administered to 10 healthy volunteers. Subject baseline plasma levels of MDA were 50 ± 20 nM. After a meal of turkey meat cutlets, plasma MDA levels increased by 160 nM (P<0.0001); after (B) there was a 75% reduction in the absorption of MDA (P<0.0001). However, after (C), the elevation of plasma MDA was completely prevented (P<0.0001). Similar results were obtained for MDA accumulation in urine. Our study suggests that red wine polyphenols exert a beneficial effect by the novel new function, absorption inhibition of the lipotoxin MDA. These findings explain the potentially harmful effects of oxidized fats found in foods and the important benefit of dietary polyphenols in the meal.—Gorelik, S., Ligumsky, M., Kohen, R., Kanner, J. A novel function of red wine polyphenols in humans: prevention of absorption of cytotoxic lipid peroxidation products.


Key Words: red muscle • malondialdehyde • human plasma • antioxidants


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
POLYPHENOLS, WHICH OCCUR BOTH in edible plants and in foodstuffs, form a substantial part of the human diet. The intake of polyphenolic compounds in a well-balanced diet that includes the recommended nine daily servings of fruits and vegetables and moderate amounts of tea, coffee, or red wine could well provide considerably more than 1000 mg of total polyphenols per day (1 , 2) . Some reported biological effects of polyphenols include antioxidant activity (3) , amelioration of cardiovascular diseases (4) , improvement of endothelial function (5) , modulation of {gamma}-glutamylcysteine synthetase expression (6) , and improvement of health and survival of mice on a high-fat diet (7) . It is well accepted that diets rich in polyphenols have health benefits (4 , 6 7 8 9) , but the absorption of polyphenols in humans is limited and the mechanisms of action of these molecules in the human body are not fully understood (1 , 8) .

Atherosclerosis is the main cause of morbidity and mortality in the Western world. Several hypotheses have been articulated to explain the initiating events in atherosclerosis, but its pathogenesis is still unclear; it seems to be a multifactorial disease, and apart from genetic susceptibility, several risk factors are hypothesized to be involved. These hypotheses include response-to-injury (10) , lipoprotein oxidation (11) , and the postprandial response to eating (12 13 14) . Atherosclerosis may result at least partly from processes that occur after ingestion of high-fat foods that contain lipid oxidation end products (ALEs), some of which are cytotoxic and genotoxic compounds such as oxycholesterol, 4-hydroxy-nonenal, and malondialdehyde (MDA) (12 , 13 , 15 , 16) . The stomach is a prime location for interaction of these compounds with other food constituents. We demonstrated that the stomach acts as a bioreactor and the gastric fluid as a medium for further dietary lipid peroxidation and/or antioxidation (17) . The gastrointestinal tract is constantly exposed to dietary oxidized food compounds produced during the processing and storage of foods (13 , 17 , 18) or during their digestion in the stomach (17) . The idea that the gastrointestinal tract is the location for the protective activity of antioxidants was presented by Halliwell et al. (19) . High-fat, high-cholesterol foods containing oxidized products affect endogenous lipoprotein production and catabolism, and lead to transient exposure of arteries to cytotoxic chylomicron remnants and ALEs (12 , 13 , 15 , 16) . Humans have been shown to excrete increased amounts of malondialdehyde in their urine after ingestion of oxidized fats (20 , 21) . Several epidemiological studies, as well as experimental data, suggest that populations on diets characterized by the Western pattern, with high intakes of high-fat red meat, processed meat, and processed and fried foods, but low in fruits and vegetables, are at high risk for the development of atherosclerosis and of several kinds of cancer, especially of the colon (9 , 22) . The present findings may shed new light on the mechanism of action of polyphenolic antioxidants in general, and suggest that the stomach and the gastrointestinal tract may be the main biological site of action for these compounds.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Chemicals and food products
2-Thiobarbituric acid (TBA) was obtained from Sigma Chemical Co. (St. Louis, MO, USA). Potassium hydroxide and potassium dihydrogen phosphate were obtained from Merck (Darmstadt, Germany). High-performance liquid chromatography (HPLC) grade methanol was obtained from J. T. Baker (Phillipsburg, NJ, USA). Red wine (Israeli "Shiraz" and "Cabernet Sauvignon") and red turkey thigh meat were purchased at commercial stores in Israel.

Subjects
A randomized crossover study was conducted with 10 healthy subjects. The study was carried out in accordance with the guidelines of the Hebrew University-Hadassah Institutional Committee for Human Clinical Trials and the approval of the Israel Ministry of Health Committee for Human Trials. All subjects gave informed consent before the study began. Subjects were excluded if they had any metabolic disorders, were taking dietary supplements, were smokers (>1 cigarette/day), were heavy exercisers (>4x30 min of aerobic exercise/wk), or were drinkers (>5 U of alcohol/wk).

The subjects comprised four men and six women with normal blood lipid and glucose levels, with a mean (±SD) age of 32 ± 4.4 years and mean body mass index (in kg/m2) 24.4 ± 2.8. Each subject consumed, in a random order, three different test meals on three different occasions separated by ≥1 wk. The subjects were asked to avoid eating meat or fish products for 3 days before the day of the experiment.

Test meals
The meat was minced for 45 s in a Magimix food processor (Robot, France), cooked as cutlets on an electric grill for 6 min until well done, divided into 250 g portions, and frozen at –80°C pending the experiment. Three test meals consisted of A, control, composed of red turkey meat cutlets (250 g) and a glass of water (200 ml); B, composed of red turkey meat cutlets (250 g) containing 750 µmol polyphenols, added after cooking, at the time of the meal (15 ml of concentrated wine), and a glass of red wine (200 ml, containing 1380 µmol of polyphenols); C, composed of red turkey meat cutlets (250 g) containing 750 µmol polyphenols, added before cooking during meat grinding (15 ml of concentrated wine to 250 g of meat), and a glass of red wine (200 ml containing 1380 µmol polyphenols). All meals were prepared in advance and kept at –80°C pending use (within 6 wk).

Concentrated wine
Concentrated wine was prepared as follows. Alcohol was evaporated from red wine in a R-200 Rotavapor (Buchi, Switzerland) under vacuum at 37°C and the alcohol-free wine was freeze-dried. The red wine concentrate was diluted with water to a polyphenol concentration of 50 mM as equivalent catechin and frozen in 15 ml aliquots at –80°C pending use in the experiment.

Postprandial experiment
After an overnight fast, subjects were asked to give a urine sample for malondialdehyde and creatinine analysis. A cannula was inserted into the vein of the forearm and a baseline (0 h) fasting blood sample was collected in EDTA-treated tubes. The subjects then ate a test meal within 30 min. Blood samples (10 ml) were drawn every hour for 6 h after the meal was eaten. Serum was separated from whole blood by centrifugation (910 g, 15 min), frozen, and kept at –80°C pending malondialdehyde determination (<1 wk). Urine was collected in a 2 L container for 6 h after the meal was eaten. Urine volume was recorded and aliquots were taken for analysis.

Determination of red wine polyphenols
The polyphenol contents of the wine and of the concentrated wine were determined with Folin-Ciocalteau reagent and calculated as catechin equivalent as described previously (17) .

Determination of malondialdehyde
Malondialdehyde was extracted from meat cutlets, plasma, and urine as described previously (23) . The supernatant was reacted with TBA and filtered through a 0.2 µm membrane. A 10 µl sample was injected into an SCL-10A VP HPLC (Shimadzu, Japan), separated with a Lichrocart column, model RP-18, 125–4S (Merck, Darmstadt, Germany), and detected with an RF-10AXL HPLC fluorescence detector (Shimadzu, Japan) set at 532 nm excitation and 553 nm emission. The mobile phase consisted of a 35:65 (v/v) mixture of methanol and 0.05 M potassium phosphate buffer, pH 7, and the flow rate was 1 ml/min. MDA standard solutions were used to generate a standard curve and to spike plasma samples for determination of the recovery.

Urine creatinine was analyzed by an enzymatic method with the Vitros creatinine slide and the Vitros 5.1 chemistry analyzer (Johnson & Johnson Gateway, Somerville, NJ, USA).

Statistical analysis
Repeated measures analysis of variance (ANOVA) was applied as a three-period crossover design using software SAS version 9.1 (Institute Inc, Cary, NC, USA), followed by application of the Student-Newman-Keuls Test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Ten healthy volunteers consumed the following meals on different days after an overnight fast: 250 g of grilled red turkey-meat cutlets (3.23 µmol MDA) and a glass of water (treatment A); similar cutlets (3.23 µmol MDA) with the addition of red wine concentrate (218 mg of polyphenols) after heating, during the meal, and 200 ml of red wine (403 mg of polyphenols) (treatment B); or cutlets (1.58 µmol MDA) that were supplemented by red wine concentrate (218 mg of polyphenols) before heating, and 200 ml of red wine (403 mg of polyphenols) (treatment C). The mean plasma MDA level of the fasting volunteers was 50 ± 20 nM. After consumption of cutlets in treatment A, postprandial levels of plasma MDA volunteers increased significantly by 160 nM after 3 h and remained high after 6 h. Drinking red wine during consumption of cutlets in treatment B reduced the absorption of MDA: its plasma concentration increased by only 40 nM after 4 h. However, consumption of cutlets soaked in red wine prior to cooking and drinking of red wine during the meal (treatment C) prevented the postprandial elevation of plasma MDA (Fig. 1 ). The area under the curve of plasma MDA levels plotted against time was 63% less for subjects who consumed cutlets and red wine. However, the most dramatic reduction of MDA absorption into the bloodstream was found in subjects who had consumed cutlets presoaked with red wine and taken red wine during the meal: this treatment completely prevented the accumulation of MDA in plasma; in some volunteers, the plasma MDA level was even reduced below baseline (Fig. 2 ).


Figure 1
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  		Figure 1. Changes in plasma MDA concentration after treatments A, B, and C. Plasma MDA concentration was evaluated every hour until 6 h after a meal: treatment A ({blacksquare}); treatment B ({blacktriangleup}); treatment C (•). Values are means ± SE of 10 subjects. For MDA levels, repeated-measures (ANOVA) give no subject effect (P=0.3511), a time effect (P<0.0001), or a meal effect (P<0.0001).


Figure 2
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  		Figure 2. Changes in area under the curve of plasma MDA concentration of volunteers after treatments A, B, and C. Plasma MDA concentration was calculated as AUC for each volunteer during a 6 h period after a meal: treatment A ({blacktriangledown}); treatment B ({equiv}); treatment C ({square}). Each letter denotes a subject. Values are means ± SD (n=3). For MDA levels, repeated-measures ANOVA gave no subject effect (P=0.2877) or meal effect (P<0.0001).

Similar results were obtained for MDA accumulation in urine (Fig. 3 ), as expressed by analysis of the urine samples from each volunteer (Fig. 4 ).


Figure 3
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  		Figure 3. Accumulation of MDA in urine collected from human volunteers after A, B, and C treatments. Each column represents the amount of secreted MDA, which was calculated on the basis of creatinine concentration in urine collected during a 6 h period after treatments. Values are means ± SE of 10 subjects, 3 measurements for each. For MDA levels, repeated-measures (ANOVA) give no subject effect (P=0.1492) and a meal effect (P=0.0001).


Figure 4
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  		Figure 4. Accumulation of MDA in urine collected from human volunteers after A, B, and C treatments. Each column represents the amount of secreted MDA, which was calculated on the basis of creatinine concentration in urine collected for 6 h after treatments. Each letter denotes a subject. Values are means ± SD of 3 measurements for each.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
For decades the role of lipids in health and disease has received increasing attention. The association between low-density lipoprotein (LDL) and atherogenesis is now firmly established. However, despite the association, native LDL particles did not appear to be atherogenic unless minimal modification had occurred. Oxidation of LDL was hypothesized by Steinberg and associates (11) to lead to this modification. Many data support the involvement of LDL in atherogenesis, although confirmation that oxidation is the requisite modification for atherogenesis is not complete and the cause of such plasma modification in vivo is uncertain (24) . We hypothesize that such LDL modification could arise from interaction with reactive carbonyls (produced endogenously or exogenously from the diet) in the plasma. In the present study we have demonstrated for the first time (to the best of our knowledge) the absorption and accumulation in human plasma of MDA from a dietary source, as well as the previously unknown action of red wine polyphenols: inhibition of absorption of the lipotoxin MDA in humans. The results revealed a relatively rapid accumulation of MDA in plasma, with a maximum level achieved 3 h after the meal. MDA is one of the most abundant lipid peroxidation cytotoxins formed in foods, especially in meat (25) , or endogenously in vivo (26 , 27) . After ingestion of peroxidized foods, animals and humans have been shown to excrete an increased amount of MDA in the urine (20 , 28) . Suomela et al. (28) found a significant increase in oxidized lipids and aldehydes in pig’s chylomicrons after ingestion of oxidized oil. Absorption of reactive carbonyl compounds from a consumed meal that contained advanced glycoxidation end products (AGEs) was also found in humans (29) . Most of the AGE contents of selected popular foods in the U.S. are derived from muscle foods and foods high in fats (30) . Reactive carbonyls seem to play a crucial role in the pathogenesis of atherosclerosis (31 , 32) . The structural and functional changes associated with in vivo modification of apoB-LDL was simulated by direct interaction of MDA with LDL (33) . Monoclonal antibodies raised against MDA-modified LDL bind to epitopes in plasma and atherosclerosis lesions (33 , 34) . MDA has also been shown to be mutagenic in mammalian and human cells (35 , 36) and to be carcinogenic in mice (37) . The pathological effects of reactive carbonyls are related to their ability to modify reactive molecules by cross-linking and to bind to several cellular receptors (9 , 31 , 38 , 39) . Such interactions with proteins and receptors could promote inflammatory mediators and result in cellular oxidative stress (31 , 38) . We assume that absorption of the MDA protein after digestion is through an N-{epsilon}-(2 propenal) lysine adduct, which retains its ability to modify proteins and DNA (31 , 38 , 40) . Lipid peroxidation processes of food, especially muscle foods, can yield a variety of reactive compounds other than MDA, such as hydroperoxides, F2-isoprostanes, oxycholesterol, and 4-hydroxy-nonenal. The present study tracked the journey of one of these cytotoxins, MDA, from the dietary source to the human body. Although isoprostanes is a specific index for lipid peroxidation, it does not appear to be absorbed from foods (41) . In contrast, MDA has been shown to be absorbed from foods (42) . In addition, it is one of the abundant peroxidation products formed in muscle foods and is highly correlated with the accumulation of hydroperoxides (17 , 43 , 44) . However, we assumed that other reactive carbonyls would exhibit a similar pattern. Our data demonstrated unequivocally that daily and cumulative exposure of the human body (e.g., its arteries, to high levels of cytotoxins) can explain the potentially harmful effects of an intake of oxidized fats found in foods, especially muscle foods. We thought that one of the major sources of these cytotoxins in the human body is our nutrition. However, the harmful results of the consumption of high-fat, partially oxidized foods can be prevented by the addition of food-derived polyphenols to the meal, as was clearly demonstrated by our results. The addition of red wine polyphenols to the meat cutlets convincingly demonstrated a dramatic reduction in the accumulation of MDA in humans. This inhibition of MDA absorption by polyphenols could be due to the prevention of lipid peroxidation in the stomach medium (17) , but it could also be due to the formation of an adduct between polyphenols and aldehydes, such as those found between polyphenols and methyl glyoxal (45 , 46) , which may prevent the absorption of these compounds in humans. Indeed, incubation of red wine polyphenols with endogenous muscle MDA reduced formation of the thiobarbituric-MDA complex by 60–70% (data not shown), a result similar to that obtained by Lo et al. (45) for interactions between tea catechins and methyl glyoxal. An additional reason might be the interaction between red wine polyphenols and proteolytic enzymes in the gastrointestinal tract. Digestion of foods with proteolytic enzymes in vitro released MDA from proteins, mainly in the form of adduct with lysine (47) . Evaluation of MDA-lysine bioavailability in rats showed incorporation mostly in the liver, small intestine, and plasma (42) . Secondary bonds formed between polyphenols and proteins (48) or enzymes (49 , 50) may also prevent digestion of the MDA-protein adduct to form MDA-lysine in the gut and so decrease MDA absorption.

In light of our present results, it can be assumed that one of the most important sites of polyphenol action is in the digestive system, before absorption.

We suggest that the main benefit of consuming plant polyphenols in the human diet as an integral part of the meal may arise from their ability to prevent generation and absorption of cytotoxic ALEs (51) , such as reactive carbonyls or other reactive compounds commonly found in our foods. Diets high in fat and red meat are contributory risk factors, whereas consumption of polyphenol-rich fruits, vegetables, and their derived beverages during the meal seems to reduce these risk factors and to provide important protective benefits for our health. Locating the biological site of action of polyphenols in the gastrointestinal tract may lead to a revision in our understanding of how antioxidants work in vivo and may help to elucidate the mechanism involved in the "French paradox" phenomena and the protective effect of the Mediterranean or the Japanese diet.


   ACKNOWLEDGMENTS
 
This research was supported by Research Grant Award IS-3647–04CR from BARD, The United States-Israel Agricultural Research and Development Fund. We thank R. Granit, M. Segev, and O. Eliav for their assistance.

Received for publication June 25, 2007. Accepted for publication July 26, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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