Nutritional Antioxidants And Polyphenolic Flavonoids

The beneficial health effects attributed to the consumption of fruits and vegetables are related, at least in part, to their antioxidant activity.12 Edible plants contain several hundred different antioxidants.3 Natural antioxidants include vitamins C and E, carotenoids (such as P-carotene and tomato's lycopene), and polyphenolic fla-vonoids (such as those present in grapes, berries, licorice, ginger, nuts, and olive oil).

For a compound to be defined as an antioxidant it must satisfy two basic conditions:

1. When present at low concentration relative to the substrate to be oxidized, it can delay, retard, or prevent autooxidation or free radical-mediated oxidation.

2. The resulting radical formed after scavenging must be stable in order to interrupt the oxidation chain reaction.

Low-density lipoprotein (LDL) oxidation is considered to be a hallmark of early atherogenesis. Nutritional antioxidants can affect LDL oxidation directly or indirectly, via modulations of arterial wall cell oxidative state and its subsequent capacity to oxidize LDL. Dietary antioxidants can inhibit LDL oxidation by several means:

1. Scavenging of free radicals, chelation of transition metal ions, or protection of the intrinsic antioxidants in the LDL particle (vitamin E and carotenoids) from oxidation.

2. Protecting cells in the arterial wall against oxidative damage and, as a result, inhibition of cell-mediated oxidation of LDL.

3. Preservation of serum paraoxonase (a high-density lipoprotein [HDL]-associated enzyme, which hydrolyzes specific lipid peroxides) activity.

Vitamin E (a-Tocopherol) has been proposed to be a very important lipid-soluble radical-scavenging antioxidant in cellular and subcellular membranes and also in plasma lipoproteins.4 In vitro studies demonstrated that vitamin E inhibits peroxyl-radical- or heme-induced LDL oxidation.56 Vitamin E supplementation to apolipo-protein E-deficient (E0) mice or to Watanabe Heritable Hyperlipidemic (WHHL) rabbits resulted in prolongation of the LDL oxidation lag time and attenuated atherosclerosis development.78 In healthy humans, vitamin E supplementation for 2 months resulted in LDL resistance to oxidation9, and in patients with carotid artery stenosis, short-term alpha-tocopherol supplementation (500 IU/day) also inhibited lipid peroxidation in the patients' atherosclerotic lesions.10

Carotenoids are natural pigments with lipophylic properties that also possess antioxidant characteristics.111213 P-carotene and lycopene are the major carotenoids in human plasma, and LDL supplementation with P-carotene or with lycopene increases its resistance to oxidation.14 Lycopene acts as an effective antioxidant against LDL oxidation in synergy with several natural antioxidants, including vitamin E, the isoflavan glabridin, and the phenolics rosmarinic and carnosic acid.15 Furthermore, enrichment of LDL in vivo with a mixture of vitamin E, P-carotene, lycopene, asthaxanthin, and lutein following a single oral supplementation resulted in the protection of LDL polyunsaturated fatty acids (PUFA) and cholesterol moieties against oxidative modification.16 The consumption by healthy adults of food products containing moderate amounts of vitamin E and carotenoids lead to a significant reduction in lipid peroxidation.1718

Flavonoids comprise the largest and most-studied group of plant antioxidants, with more than 4000 different flavonoids being identified to date. They are usually found in plants as glycosides, and large compositional differences exist between different types of plants, even between different parts of the same plant.19 Flavonoids are grouped into anthocyanins and anthoxantins. Anthocyanins are glycosides of anthocyanidin and are the most important group of water-soluble plant pigments, responsible for the red, blue, and purple colors of flowers and fruits. Anthoxantins are colorless or colored white-to-yellow, and include flavonols, flavanols, flavones, flavans, and isoflavones.

Flavonoids are powerful antioxidants against LDL oxidation, and their activity is related to their localization in the LDL particle, as well as to their chemical structure.20-24 Flavonoids are effective scavengers of hydroxyl and peroxyl radicals, as well as of superoxide anion.2526 Some act also as antioxidants due to their potent chelation capacity of transition metal ions.2627 Furthermore, flavonoids can preserve serum paraoxonase 1 (PON1) activity probably as a result of the reduction in the level of oxidized lipids.28,29 Flavonoids are also quite suitable for protecting cell membranes from free-radical-induced oxidation, since they are both lipophilic and hydrophilic and thus are able to scavenge free radicals, which are generated within the cells, as well as free radicals that attack the cell membrane from the outside. Indeed, flavonoids were shown to reduce macrophage oxidative stress and cellmediated oxidation of LDL.30

We have performed in vitro and ex vivo studies in humans and in the atherosclerotic E0 mouse, and in a cell-free system, which demonstrated that the licorice root extract and its purified isoflavane glabridin protected LDL against macrophage-induced oxidation.31-35 Flavonols and their glycosides are effective antioxidants against 2,2'-azobis 2-amidino-propane dihydrochloride (AAPH- free-radical generator) and copper ion-induced LDL oxidation. The flavonols bearing the orthodihy-droxyl groups possess significantly higher antioxidative activity than those bearing no such functionalities. The flavonol glycosides are less effective in this respect.36 Red wine and its flavonol quercetin were shown to inhibit LDL oxidation in both water and lipid-soluble free-radical-generating systems.37,38 We have previously shown that preparation of white wine from whole squeezed grapes in the presence of 18% alcohol remarkably increased the extraction of grape skin polyphenols into the produced white wine, paralleled by an improvement of the white wine antioxidant activity, up to a similar extent to that present in red wine.39 Red wine consumption by healthy subjects increased the resistance of LDL to oxidation,40,41 and this effect depends on the polyphenol composition of the red wine.42 Grape seeds extract also possesses antioxidative properties, as it was shown to reduce LDL oxidation in heavy smokers, who are under oxidative stress.43 In E0 mice under oxidative stress, supplementation of grape powder polyphenols, or red wine or its polyphenols quercetin or catechin, decreased LDL oxidation and attenuated atherosclerosis development.44-47 The pomegranate tree, which is said to have flourished in the Garden of Eden, has been extensively used as a folk medicine in many cultures. The fruit of the pomegranate (~50% of total pomegranate weight) consists of 80% juice and 20% seeds. The fresh juice contains 85% water, 10% total sugars, 1.5% pectin, ascorbic acid, and polyphenolic flavonoids.48,49 In pomegranate juice (PJ), fructose and glucose are present in similar quantities (but it contains additional complexed, as-yet-unidentified sugars), calcium is 50% of its ash content, and the principal amino acids are glutamic and aspartic acids.50 The soluble polyphenol content varies within the limits of 0.2 to 1.0%, and includes mainly ellagic tannins, gallic and ellagic acids, anthocyanins, and catechins.51,52 Consumption of PJ by humans (one 8-oz [240-ml] glass a day) for a period of one year significantly increased PON1 activity and reduced the oxidation of both LDL and HDL by up to 60%. Most of these effects were already achieved in the first month of juice consumption.53 Studies of patients with carotid artery stenosis (blockage in the arteries that supply blood to the brain) who consumed PJ for 3 years clearly demonstrated reduced oxidative stress in their blood, increased PON1 activity (by 83%), and, most importantly, a decreased atherosclerotic lesion size (by 30%).54 Similarly, in E0 mice supplemented with PJ, serum oxidative stress, macrophage-mediated oxidation of LDL, and the progression of atherosclerotic lesion were significantly inhibited.53 55 Similarly, in a recent study, oral administration of PJ to hypercholesterolemic mice at various stages of the disease significantly reduced the progression of atherosclerosis. This effect of PJ could be attributed to its effect on oxidation-sensitive genes and on endothelial NO synthase activity at the site of perturbed shear stress.56

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