Flavonoids As Antioxidants
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J. Nat. Prod. 2000, 63, 1035-1042 1035 Reviews Flavonoids as Antioxidants Pier-Giorgio Pietta* Institute of Advanced Biomedical Technologies, National Council of Research Via F.lli Cervi 93, 20090 Segrate (MI), Italy Received September 13, 1999 Flavonoids are phenolic substances isolated from a wide range of vascular plants, with over 8000 individual compounds known. They act in plants as antioxidants, antimicrobials, photoreceptors, visual attractors, feeding repellants, and for light screening. Many studies have suggested that flavonoids exhibit biological activities, including antiallergenic, antiviral, antiinflammatory, and vasodilating actions. However, most interest has been devoted to the antioxidant activity of flavonoids, which is due to their ability to reduce free radical formation and to scavenge free radicals. The capacity of flavonoids to act as antioxidants in vitro has been the subject of several studies in the past years, and important structure-activity relationships of the antioxidant activity have been established. The antioxidant efficacy of flavonoids in vivo is less documented, presumably because of the limited knowledge on their uptake in humans. Most ingested flavonoids are extensively degraded to various phenolic acids, some of which still possess a radical- scavenging ability. Both the absorbed flavonoids and their metabolites may display an in vivo antioxidant activity, which is evidenced experimentally by the increase of the plasma antioxidant status, the sparing effect on vitamin E of erythrocyte membranes and low-density lipoproteins, and the preservation of erythrocyte membrane polyunsaturated fatty acids. This review presents the current knowledge on structural aspects and in vitro antioxidant capacity of most common flavonoids as well as in vivo antioxidant activity and effects on endogenous antioxidants. Introduction it, such as heart disease, cataracts, cognitive dysfunction, and cancer.4-6 Humans have evolved with antioxidant Oxidation is the transfer of electrons from one atom to systems to protect against free radicals. These systems another and represents an essential part of aerobic life and include some antioxidants produced in the body (endog- our metabolism, since oxygen is the ultimate electron acceptor in the electron flow system that produces energy enous) and others obtained from the diet (exogenous). The in the form of ATP.1 However, problems may arise when first include (a) enzymatic defenses, such as Se-glutathione the electron flow becomes uncoupled (transfer of unpaired peroxidase, catalase, and superoxide dismutase, which single electrons), generating free radicals. Examples of metabolize superoxide, hydrogen peroxide, and lipid per- oxides, thus preventing most of the formation of the toxic oxygen-centered free radicals, known as reactive oxygen • •- • HO , and (b) nonenzymatic defenses, such as glutathione, species (ROS), include superoxide (O2 ), peroxyl (ROO ), alkoxyl (RO•), hydroxyl (HO•), and nitric oxide (NO•). The histidine-peptides, the iron-binding proteins transferrin hydroxyl (half-life of 10-9 s) and the alkoxyl (half-life of and ferritin, dihydrolipoic acid, reduced CoQ10, melatonin, seconds) free radicals are very reactive and rapidly attack urate, and plasma protein thiols, with the last two ac- the molecules in nearby cells, and probably the damage counting for the major contribution to the radical-trapping caused by them is unavoidable and is dealt with by repair capacity of plasma. The various defenses are complemen- processes. On the other hand, the superoxide anion, lipid tary to each other, since they act against different species hydroperoxides, and nitric oxide are less reactive.2 In at different cellular compartments. However, despite these addition to these ROS radicals, in living organisms there defense antioxidants (able either to suppress free radical 1 formation and chain initiation or to scavenge free radical are other ROS nonradicals, such as the singlet oxygen ( O2), and chain propagation), some ROS still escape to cause hydrogen peroxide (H2O2), and hypochlorous acid (HOCl). It is accepted that ROS play different roles in vivo. Some damage. Thus, the body antioxidant system is provided also are positive and are related to their involvement in energy by repair antioxidants (able to repair damage, and based on proteases, lipases, transferases, and DNA repair en- production, phagocytosis, regulation of cell growth and 7 intercellular signaling, and synthesis of biologically im- zymes). portant compounds.3 However, ROS may be very damaging, Owing to the incomplete efficiency of our endogenous since they can attack lipids in cell membranes, proteins in defense systems and the existence of some physiopatho- tissues or enzymes, carbohydrates, and DNA, to induce logical situations (cigarette smoke, air pollutants, UV oxidations, which cause membrane damage, protein modi- radiation, high polyunsaturated fatty acid diet, inflamma- fication (including enzymes), and DNA damage. This tion, ischemia/reperfusion, etc.) in which ROS are produced oxidative damage is considered to play a causative role in in excess and at the wrong time and place, dietary aging and several degenerative diseases associated with antioxidants are needed for diminishing the cumulative effects of oxidative damage over the life span.8,9 Well- * To whom correspondence should be addressed. Tel.: 0039 02 26422725. established antioxidants derived from the diet are vitamins Fax: 0039 02 26422770. E-mail: [email protected]. C, E, A, and carotenoids, which have been studied inten- 10.1021/np9904509 CCC: $19.00 © 2000 American Chemical Society and American Society of Pharmacognosy Published on Web 05/27/2000 1036 Journal of Natural Products, 2000, Vol. 63, No. 7 ROS produced by the photosynthetic electron transport system.20 Furthermore, because of their favorable UV- absorbing properties, flavonoids protect plants from UV radiation of sun and scavenge UV-generated ROS.21 Apart from their physiological roles in the plants, fla- vonoids are important components in the human diet, although they are generally considered as nonnutrients. Indeed, the level of intake of flavonoids from diet is Figure 1. Basic flavonoid structure. considerably high as compared to those of vitamin C (70 mg/day), vitamin E (7-10 mg/day), and carotenoids (â- sively.10 Besides these antioxidant vitamins, other sub- carotene, 2-3 mg/day).22 Flavonoid intake can range stances in plants might account for at least part of the between 50 and 800 mg/day, depending on the consumption health benefits associated with vegetable and fruit con- of vegetables and fruit, and of specific beverages, such as sumption. Over the past decade evidence has been ac- red wine, tea, and unfiltered beer.23 In particular, red wine cumulated that plant polyphenols are an important class and tea contain high levels (approximately 200 mg per of defense antioxidants. These compounds are widespread glass of red wine or cup of tea) of total phenols. Thus, virtually in all plant foods, often at high levels, and include variations in consumption of these beverages are mainly phenols, phenolic acids, flavonoids, tannins, and lignans. responsible for the overall flavonoid intake in different Flavonoids. Flavonoids are formed in plants from the national diets. Another significant source of flavonoids are aromatic amino acids phenylalanine and tyrosine, and different medicinal plants and related phytomedicines.24 malonate.11 The basic flavonoid structure is the flavan nucleus, which consists of 15 carbon atoms arranged in Epidemiological Evidence. Several epidemiological studies provide support for a protective effect of the three rings (C6-C3-C6), which are labeled A, B, and C (Figure 1). The various classes of flavonoids differ in the consumption of fresh fruits and vegetables against can- 25,26 27-29 30,31 level of oxidation and pattern of substitution of the C ring, cer, heart disease, and stroke. Normally, high while individual compounds within a class differ in the consumers of fruits and vegetables have a healthy lifestyle, pattern of substitution of the A and B rings. Among the which may be an important factor for their resistance many classes of flavonoids, those of particular interest to against chronic diseases. All in all, fruits and vegetables this review are flavones, flavanones, isoflavones, flavonols, do play a preventive role, which is due to a variety of flavanonols, flavan-3-ols, and anthocyanidins (Table 1). constituents, including vitamins, minerals, fiber, and nu- Other flavonoid classes include biflavones, chalcones, au- merous phytochemicals, including flavonoids. Thus, it is rones, and coumarins. Hydrolyzable tannins, proantho- possible that also flavonoids contribute to the protective cyanidins (flavan-3-ol oligomers), caffeates, and lignans are effect of fruits and vegetables. This possibility has been 32 all plant phenols, and they are usually classified separately. evidenced by several in vitro, ex vivo, and animal studies. Flavonoids generally occur in plants as glycosylated Unfortunately, the evidence in humans is still limited and 33 derivatives, and they contribute to the brilliant shades of somewhat controversial. Data on biological markers, such blue, scarlet, and orange, in leaves, flowers, and fruits.12 as blood levels of flavonoids and their metabolites, are not Apart from various vegetables and fruits, flavonoids are widely available, thus making it difficult to determine the found in seeds, nuts, grains,