Recent Updates on Free Radicals Scavenging Flavonoids: An Overview
Vivek Kumar Gupta,
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.
Received: January 28, 2010;
Accepted: March 17, 2010;
Published: June 02, 2010
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.
||Chemical structures of the major classes of flavonoids
|| Major food sources of flavonoids
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).
|| Dietary sources of flavonoids
||Description of some important flavonoidal drugs
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).
|| Flavonoidal content of tea
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).
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).
|| Scavenging of ROS (R*) by flavonoids
||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).
||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).
|| Diseases treated with flavonoids
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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.,
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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