Antioxidant Activity of Flavonoids and Phenolic Acids

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Free radicals are produced in the body as part of normal metabolism, for example superoxide, O2~- and nitric oxide, NO- which have important physiological functions. In general, free radicals are highly reactive and can attack membrane lipids for example, generating a carbon radical which in turn reacts with oxygen to produce a peroxyl radical which may attack adjacent fatty acids to generate new carbon radicals. This process leads to a chain reaction producing lipid peroxidation products (Halliwell, 1994). By this means a single radical may damage many molecules by initiating lipid peroxidation chain reactions. Because of the potential damaging nature of free radicals, the body has a number of antioxidant defence mechanisms which include enzymes such as superoxide dismutase, catalase, copper and iron transport and storage proteins, and both water-soluble and lipid-soluble molecular antioxidants. Oxidative stress may result when antioxidant

Table 9.1. Some dietary sources of flavonoids and phenolic acids.

Flavonoid Source

Catechins Tea, red wine

Flavanones Citrus fruits

Flavonols (e.g. Quercetin) Onions, olives, tea, wine, apples

Anthocyanidins Cherries, strawberries, grapes, coloured fruits

Caffeic acid Grapes, wine, olives, coffee, apples, tomatoes, plums, cherries defences are unable to cope with the production of free radicals, and may result from the action of certain toxins or by physiological stress (Halliwell,

Flavonoids and phenolic acids can act as antioxidants by a number of potential pathways. The most important is likely to be by free radical scavenging in which the polyphenol can break the free radical chain reaction. For a compound to be defined as an antioxidant it must fulfil two conditions: (i) when present at low concentrations compared with the oxidizable substrate it can significantly delay or prevent oxidation of the substrate; (ii) the resulting radical formed on the polyphenol must be stable so as to prevent it acting as a chain propagating radical (Halliwell et al.,

1995). This stabilization is usually through delocalization, intramolecular hydrogen bonding or by further oxidation by reaction with another lipid radical (Shahidi and Wanasundara, 1992). A number of studies have been carried out on the structure-antioxidant activity relationships of the flavonoids (Bors et al., 1990; Chen et al., 1996; Rice-Evans et al., 1996; Van Acker et al., 1996; Cao et al., 1997). The main structural features of flavonoids required for efficient radical scavenging could be summarized as follows:

1. An ortho-dihydroxy (catechol) structure in the B ring, for electron delocalization;

2. A 2,3 double bond in conjugation with a 4-keto function, provides electron delocalization from the B ring;

3. Hydroxyl groups at positions 3 and 5, provide hydrogen bonding to the keto group.

These structural features are illustrated in Fig. 9.4.

The phenolic acids may also be good antioxidants, particularly those possessing the catechol-type structure such as caffeic acid (Laranjinha et al., 1994; Nardini et al., 1995; Abu-Amsha et al., 1996). Recent studies have indicated that simple cell-derived phenolic acids such as 3-hydroxyanthranilic acid may also be efficient co-antioxidants for a-tocopherol, able to inhibit lipoprotein and plasma lipid peroxidation in humans (Thomas et al., 1996). The possible interaction between flavonoids and phenolic acids with other physiological antioxidants such as ascorbate or tocopherol is another possible antioxidant pathway for these compounds. The synergistic interaction of these antioxidants may be exemplified by the enhancement of the antiproliferative effect of quercetin by ascorbic acid, possibly due to its ability to protect the polyphenol from oxidative degradation (Kandaswami et al., 1993). In a similar manner, coincubation of low-density lipoprotein (LDL) with ascorbate and caffeic or coumaric acid resulted in a synergistic protection from oxidation promoted by ferrylmyoglobin (Vieira et al., 1998a).

Another pathway of apparent antioxidant action of the flavonoids, particularly in oxidation systems using transition metal ions such as copper or iron, is chelation of the metal ions. Chelations of catalytic metal ions may

HO O

OH

..OH

OH

CJL 1 11

^O

i O 0 --

-H-'

1 ''H''

Fig. 9.4. Structural groups for radical scavenging.

prevent their involvement in Fenton-type reactions which can generate highly reactive hydroxyl radicals (reactions 9.1 and 9.2) (Halliwell et al., 1995).

The ability of polyphenolics to react with metal ions may also render them pro-oxidant. For example, in a recent study by Cao et al. (1997) using three diffferent oxidation systems, flavonoids had potent antioxidant activity against peroxyl radicals generated from AAPH and against hydroxyl radicals but were pro-oxidant with Cu2+. Presumably flavonoids can reduce Cu2+ to Cu+ and hence allow the formation of initiating radicals. Caffeic acid has also been shown to have pro-oxidant activity on Cu2+-induced oxidation of LDL (Yamanaka et al., 1997). It should be noted that this pro-oxidant activity was seen only in the propagation phase of the oxidation, not in the initiation phase in which caffeic acid inhibited lipoprotein oxidation, in agreement with previous findings (Laranjinha et al., 1994; Nardini et al., 1995; Abu-Amsha et al., 1996).

The possible pro-oxidant effects of flavonoids may be important in vivo if free transition metal ions are involved in oxidation processes. In the healthy human body, metal ions appear largely sequestered in forms that are unable to catalyse free radical reactions (Halliwell and Gutteridge, 1990).

However, injury to tissues may release iron or copper (Halliwell et al., 1992) and catalytic metal ions have been measured in atherosclerotic lesions (Smith et al., 1992). In these cases the potential for flavonoids to act as pro-oxidants cannot be ignored.

Other biological actions of phenolic compounds have been noted which may be relevant to their effects on human health. For example, caffeic acid may have cytoprotective effects on endothelial cells related not only to its antioxidant action but also to its ability to block the rise in intracellular calcium in response to oxidized lipoproteins (Vieira et al., 1998b). Some phenolic compounds may also inhibit platelet aggregation (Pace-Asciak et al., 1996), while others may act as inhibitors of nuclear transcription factor NF-kB (Natarajan et al., 1996). The ability of phenolic compounds to trap mutagenic electrophiles such as reactive nitrogen species may also protect biological molecules from damage (Kato et al., 1997).

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