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Asian Journal of Plant Sciences

Year: 2010 | Volume: 9 | Issue: 3 | Page No.: 108-117
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Research Article

Recent Updates on Free Radicals Scavenging Flavonoids: An Overview

Vivek Kumar Gupta, Rachna Kumria, Munish Garg and Monika Gupta

ABSTRACT

Flavonoids are low molecular weight, polyphenolic compounds present in majority of vascular plants, possessing many therapeutic activities vis a vis antioxidant activity. The present review discuss the chemical nature, mechanism of action, current status, pharmacodynamic/pharmacokinetic studies, industrial significance, nutritive value in health system and analysis of flavonoids with the recent technology.
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Received: January 28, 2010;   Accepted: March 17, 2010;   Published: June 02, 2010

INTRODUCTION

Reactive Oxygen Species (ROS) including superoxide radicals, hydroxyl radicals, singlet oxygen and hydrogen peroxide are often generated as byproducts of biological reactions or from exogenous factors (Cerutti, 1991). These ROS may be very damaging and attack lipids in cell membranes and also attack DNA, inducing oxidation that causes membrane damage such as membrane lipid peroxidation (Cerutti, 1994; Pietta, 2000; Kumar and Sharma, 2006). Lipid peroxidation has been implicated in the pathogenesis of a number of diseases like arthritis (Naik, 2003), diabetes (Yagi, 1987), cancer (Rekha et al., 2001), atherosclerosis (Tiwari, 2001), neurodegenerative diseases (Thomas and Kalyanaraman, 1997), etc. Definitely, many synthetic antioxidant components have shown toxic and/or mutagenic effects, which have shifted the attention onto the naturally occurring antioxidants (Gupta and Sharma, 2010a,b; Kumar and Sharma, 2006). Flavonoids and their synthetic analogues have been intensely investigated and found the prominent role in the treatment of ovarian, breast, cervical, pancreatic and prostate cancer, in recent years. Their use has mainly centred on prevention and the maintenance of health (Aruoma and Cuppet, 1997). The recognized dietary antioxidants are vitamin C, vitamin E, selenium, carotenoids (beta carotene), etc. However, recent studies have demonstrated that flavonoids found in fruits and vegetables may also act as antioxidants. Like alpha-tocopherol (vitamin E), flavonoids contain chemical structural element that may be responsible for their antioxidant activities (Di Carlo et al., 1999). Flavonoids generally occur in plants as glycosylated derivatives and impart different color shades (blue, scarlet and orange in leaves, flowers and fruits (Brouillard and Cheminat, 1988). Flavonoids are major components of citrus fruits and several other medicinal plants and have been used in traditional medicine around the world (Winston, 1999; Di Carlo et al., 1999; Kadarian et al., 2002; Pascual et al., 2001; Samuelsen, 2000). Many families have been reported to have isoflavonoids in addition to Leguminosae. The spectrum of isoflavonoid producing taxa includes the representatives of four classes of multicellular plants, namely the Bryopsida, the Pinopsida, the Magnoliopsida and the Liliopsida. Isoflavonoids in non-leguminous families provided listing of 164 isoflavonoids altogether reported in 31 non-leguminous angiosperm families (Mackova et al., 2006).

CHEMICAL NATURE OF FLAVONOIDS

Flavonoids are polyphenolic compounds are ubiquitous in nature and categorized into many classes according to their chemical structure. Over 4000 flavonoids have been identified, many of which occur in the fruits, vegetables and beverages (tea, coffee, beer, wine and fruit drinks) (Aruoma and Cuppet, 1997). The flavones apigenin (3b) and luteolin (3a) are common in cereals grains and in aromatic herbs viz., rosemary, thyme, parsley etc. (Pietta et al., 1995). The flavonols quercetin (4b) and kaempferol (4c) are usually present in vegetables and fruits. Flavonoids are formed in the plants from the aromatic amino acids phenylalanine and tyrosine and malonate. Isoflavones are found mostly in legumes (soyabeans, black beans, green beans and chick peas) (Herman, 1976). Flavan oligomers (proanthocyanidins) are found in apples, grapes, berries, barley grains etc. (Franke et al., 1994). Anthocyanidins and their glycosides (anthocyanins) are abundant in berries and red grape (Haslam, 1989). Some major food sources (Hollman and Katan, 1999) are given in Table 1.

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Fig. 1: Chemical structures of the major classes of flavonoids

Table 1: Major food sources of flavonoids
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The basic structural unit of the flavonoid family comprises two benzene rings (A and B) (1) as shown in Fig. 1 linked through a heterocyclic pyran or pyrone ring (C), variation in the C ring and hydroxylation pattern on the A and B rings define the major classes (Cook and Samman, 1996) including Isoflavones (genistein) (2a), Flavones (luteolin) (3a), Flavonols (quercetin) (4b), Flavan-3-ols (epicatechin) (5b), Flavanones (naringenin) (6a), Anthocyanidins (cyanidin) (7). The in vitro anticancer assay with synthetic compounds of structurally related subcategories of flavonoids (viz., flavones, isoflavones, xanthones) indicated the maximum activity with xanthones and least with isoflavones, however, flavones exhibited more significant activity than isoflavones and less significant when compared with xanthones (Wang et al., 2005).

DIETARY AND INDUSTRIAL SIGNIFICANCE OF FLAVONOIDS

The flavonoids exert potential beneficial effects on health (Table 2), extensively employed in the various formulations in the industry and may also be obtained from the diet (dietary flavonoids). In addition to outstanding anti-oxidant activity, flavonoids possess a profound inhibitor action on the formation of lipid peroxides both in vitro (Carini et al., 1992; Villa et al., 1992) as well as in vivo (Chen et al., 1990; Cholbi et al., 1991; Uchida et al., 1988). However, the range of dietary flavonoids varies from low content (<1 mg/100 g) to high content (5-35 mg/100 g) depending upon the biological source (Table 3). Quercetin, kaempferol, myricetin, luteolin, apigenin are some important examples of flavonoids, present in the dietary sources (Hertog et al., 1992, 1993). In addition to these dietary sources, there are a number of plants, which are not the part of diet, used in therapeutics, but having appreciable flavonoidal content like beverages such as wine (red wine), tea, beer etc. (Larson, 1988). Flavonoids are present in a number of drugs/plants, they may occur in any part of the plant but, generally found in more concentration in leaves or flowers (Table 4).

Table 2: Flavonoids showing activities other than antioxidant activity
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Table 3: Dietary sources of flavonoids
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Table 4: Description of some important flavonoidal drugs
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Rutin, a flavonoid, bearing pronounced therapeutic activity, widely used in the industry. It is well documented the plants viz. Saphora japonica L. (Fabaceae), Fagopyrum esculentum Moench. (Polygonaceae), Eucalyptus macrorrhynca F. Muell. (Myrtaceae) are been used at large in industry for extraction of rutin (Bruneton, 1995). Flavonoids, tannins and/or polyphenolic compounds found in some Ficus spp. also showed antoxidant or free radicals scavenging activity (Sharma and Gupta, 2007a, b, 2008).

PHARMACOKINETIC/PHARMACODYNAMIC STUDIES OF FLAVONOIDS

It has been proved that flavonoids from dietary sources exert significant antioxidant effect. It is believed that flavonol, flavone and isoflavone glycosides are initially hydrolyzed to their respective aglycones (Manach et al., 1996; Nielsen et al., 1997).

Table 5: Flavonoidal content of tea
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The glycoside quercetin-3-rutinoside was detected in the blood (after consumption of tomato puree) (Mauri et al., 1999), naringin (4’, 5, 7-trihydroxyflavanone-7-rhamnoglucoside) in urine (after taking naringin orally) (Ishii et al., 2000), epigallocatechin gallate and epicatechin gallate detected in human blood after intake of green tea (green tea has more flavonoidal content as compare to black tea (Anonymous, 1991) (Table 5), decaffeinated green tea extracts and dark chocolates (Michelle et al.,1999; Nakagawa and Miyazawa, 1997; Unno et al., 1996). So, all these facts support that glycosides are absorbable.

Absorption of flavonoids (flavonols, flavones, isoflavones and catechins) in the human body takes place in two ways; first, a small portion of it transformed into their glucouronides and sulfates (King and Brusill, 1998). This small fraction of the absorbed flavonoids is metabolized by the liver enzymes, resulting in more polar conjugates being excreted in the urine or returned to the duodenum via gall bladder. However, the major part of the ingested flavonoids is not absorbed and is largely degraded by the intestinal microflora. The bacterial enzymes catalyze several reactions including hydrolysis, dehydrogenation, cleavage of the heterocyclic oxygen containing ring, decarboxylation etc. In this way several phenolic acids are produced (Pietta et al., 1997). These phenolic acids can be reabsorbed and account a large fraction of the ingested flavonoids (30-60%). Phenolic acids bearing catechol structure possess a radical scavenging ability comparable to that of their intact precursors (Merfort et al., 1996).Further, TEAC values of these metabolites confirm their antioxidant potential (Pietta et al., 2000).

Flavonoids/polyphenolic rich su bstances of natural origin will always exert beneficial therapeutic effects, is not true all times. The most suitable example is tree nuts, a rich source of tocopherols, total phenols, containing wide variety of flavonoids and proanthocyanidins, has not been reported significant antioxidant in vivo (Bolling et al., 2010). Absorption is the other important aspect, which could not be neglected as there are many flavonoids which are poorly absorbed and could not justify their therapeutic potential. So, this area needs to be explored further. However, The clinical applicabilities of polyphenols and other poorly absorbed plant medicines can be improved by phytosome technology which creates intermolecular bonding between individual polyphenol molecules and one or more molecules of the phospholipids, phosphatidylcholine (Kidd, 2009). Research based on strategies to determine phenolic acids and flavonoids in biological fluids, beverages, plant and food exudates may explore the applications in a better way, which is need of the day.

MECHANISM OF ACTION

The free radical scavenging activity of flavonols, flavones and anthocyanins have been reported through various in vitro models (Afanasev et al., 1989; Cui et al., 2002; Dobask et al., 1999; Duthie and Doboson, 1999; Formica and Regelson, 1995; Kerr et al., 1999; Mahesh and Menon, 2004; Pataki et al., 2002; Pietri et al., 1997; Yamashiro et al., 2003). Flavonoids act as antioxidant due to having more number of target sites for free radicals in the oligomeric compounds produced from their semiquinone radicals (Rohdewald, 2002; Bors and Michel, 1999; Bors et al., 2000; Robak and Gryglewski, 1988). Chemically, flavonoids are single electron donors. In in vitro cell culture, flavonoids have good antioxidant potential as they serve as derivative of conjugated ring structures and hydroxyl groups. They act as antioxidant by scavenging superooxide anion (Husain et al., 1987), singlet oxygen (Wang and Goodman, 1999) and lipid peroxyl radicals (Fuchs et al., 1989; Lotito and Frei, 2004).

In addition to their free radical scavenging activity, flavonoids enhance intracellular antioxidant defense against free radicals by increasing production of antioxidative enzymes (Bayeta and Lau, 2000; Kandaswami and Middleton, 1994; Lewis, 1993; Wei et al., 1997). Flavonoids inhibit the enzymes responsible for superoxide anion production, such as xanthine oxidase (Hanasaki et al., 1994) and protein kinase C (Ursini et al., 1994). Flavonoids have also been shown to inhibit cyclooxygenase, lipoxygenase, microsomal monooxygenase, glutathione S-transferase, mitochondrial succinoxidase and NADH oxidase, all involved in reactive oxygen species generation (Brown et al., 1998; Korkina and Afanasev, 1997).

Due to their lower redox potentials (Jovanoic et al., 1994) flavonoids (Fl-OH) are thermodynamically able to reduce highly oxidizing free radicals with redox potentials in the range 2.13-1.0 V (Buettner, 1993), such as superoxide, peroxyl, alkoxyl and hydroxyl radicals by hydrogen atom donation:where, R• represents superoxide anion, peroxyl, alkoxyl and hydroxyl radicals (Husain et al., 1987; Robak and Gryglewski, 1988; Terol et al., 1986). The aroxyl radical (Fl-Oÿ) may react with second radical, acquiring a stable quinone structure (Fig. 2).

Fl-OH + R• Fl-O + RH

The aroxyl radicals could interact with oxygen, generating quinines and superoxide anion, rather than terminating chain reactions. The last reaction may take place in the presence of high levels of transient metal ions and is responsible for the undesired prooxidant effect of flavonoids (McCord, 1995). So, it shows the flavonoids to act as antioxidants depends not only on the redox potential of the couple Fl-O•/Fl-OH but also on possible side reactions of the aroxyl radical. Scavenging of superoxide is particularly important, because the radical is ubiquitous in aerobic cells and, despite its mild activity, is a potential precursor of the hydroxyl radical in the Fanton and Haber-Weiss reactions (Cao et al., 1997).

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Fig. 2: Scavenging of ROS (R*) by flavonoids

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Fig. 3: Flavonoids lead to brain development by targeting astrocytes

Flavonoids present in diet are natural antioxidants and possess the potential to stabilize various radicals (oxygen-cenered, carbon-centered, alkoxyl peroxyl, or phenoxyl radicals) and ROS involved in oxidative processes through hydrogenation or complexing with oxidizing species (Nones et al., 2010; Shahidi and Wanasundara, 1992).

Some scientists strongly believe that the physiological benefits of flavonoids is not due to their antioxidant and free radical scavenging effects rather to their capability to target to astrocytes especially in brain development, as astrocytes are pivotal characters in neurodegenerative diseases and brain injury (Fig. 3) (Hackl et al., 2002).

ANALYSIS OF FLAVONOIDS

There are many reports that plant-derived phenolic compounds such as flavonoids have antioxidant properties capable of reducing the risk of developing age related diseases such as atherosclerosis, Alzheimer and osteoarthritis. Many herbal formulation have been prepared and therapeutic effects and flavonoidal content was successfully analyzed through thin-layer chromatography and high performance thin layer chromatography (Pendry et al., 2005).

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Fig. 4: Various techniques involved in analysis of flavonoids

A study was conducted in Taiwan on harvested soybeans to determine major and minors of isoflavones, after subjected to methanol-H(2)O extraction and HPLC analysis with the acetic acid-acetonitrile mobile phase. Among the detected soybeans, daidzin, genistin, malonyldaidzin and malonylgenistin were the majors and glycitin, malonylglycitin, daidzein and genistein were the minors of isoflavones (Tsai et al., 2007). Flavonoids can also be satisfactorily determined by capillary electrophoresis with wall-jet amperometric detection by monitoring the effects of several important factors, such as the running buffer and its corresponding pH and concentration, separation voltage, injection time to acquire the optimum conditions for separation of the flavonoids (Fig. 4) (Xu et al., 2006).

It is well documented that flavonoids (quercetin, rutin, etc.) after absorption produce good therapeutic effect in a number of other ailments also, apart from antioxidant activity (Table 6).

NUTRITIVE VALUE OF FLAVONOIDS

The flavonoids have been used over a period of time in other ailments (Table 2, 6) except as an antioxidant. Tea, the top drink in the world, has flavonoids which act as antioxidants. Apple provides the most concentrated food source of flavonoids, a group of phytochemicals, believed to protect against cancer, heart disease and other serious health problems, lending some truth to the old adage an apple a day keeps the doctor away. Blueberries are another good source of antioxidants, especially good for healthy eyesight. Recent studies have found that chocolate may actually be a healthy food because it provides plenty of flavonoids which are reported to be more effective than tea. Soybean isoflavones are structurally similar to estrogen and exhibit weak estrogenic activity (Ishimi, 2009).

Table 6: Diseases treated with flavonoids
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It was claimed after experimentation on female rats that the administration of a soy extract containing isoflavones prevents oxidative changes in hepatocytes isolated from old ovariectomized female rats, without modifying uterus weight (Castillo et al., 2006). Some epimeric new triterpenoid such as 3alpha-hydroxy-20-oxo-30-norlupane and new flavanone (nubatin; 3) have not been successfully isolated from Salvia species rather these metabolites were found to be moderately bio-active also (Ali et al., 2005).

CONCLUSION

Vitamin C, E, selenium, carotenoids are well known antioxidants however they do not come under flavonoids but constitute a vital part of our diet. The total daily intake of these dietary antioxidants is quite low, vitamin C (70 mg), vitamin E (7-10 mg) or carotenoids (2-3 mg) as compared to the flavonoids (50-800 mg), which makes a substantial contribution to the antioxidant defense system. There is adequate clinical evidence that flavonoids exert crucial therapeutic effects, many of which have been used in traditional systems of medicine for thousands of years. But, their full potential is yet to be recognized in all aspects. The utility of flavonoids in medicines should be elaborated. More pharmacokinetic and pharmacodynamic studies are required to define the protective role of flavonoids by scavenging free radicals in the mammalians.

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