Flavonoid reactivities

Structural identification of anthocyanin derived pigments and the studies carried out on their mechanisms of formation allowed us to bring out a general pattern of the flavonoid reactivities (figure 2). Basically, flavonoids are built on a three-ring core consisting of A and B aromatic systems bearing hydroxyl... 

Based on the flavonoid reactivity pattern (figure 2), the dichotomy between electrophilic and nucleophilic characters is strongly related to pH. The more acidic the pH is, the more cationic charges prevail. Thus, the balance between flavylium cations (AH+) and hydrated forms (AOH) is pH-dependent as well as the interflavanic bond cleavage yielding the flavanol cations (F+). In addition, acetaldehyde protonation is also controlled by pH. Therefore, it can be expected that reactions involving flavylium, flavanol or protonated acetaldehyde cations are favored at lower pH values. Based on carbocation reactivity, these cationic species can be classified as follows ... 

As strong metal ion chelators due to their catechol structure, tea flavonoids are able to bind and thus decrease the level of free cellular ferric and ferrous ions, which are required for the generation of reactive oxygen radicals via the Fenton reaction (Yang and Wang, 1993). 

CANADA A T, GiANNiLLA E, NGUYEN J D and MASON R p (1990) The production of reactive oxygen species by dietary flavonoids, Free Rad Biol Med, 9, 441-9. 

Colquhoun and Schumacher [98] have shown that y-linolcnic acid and eicosapentaenoic acid, which inhibit Walker tumor growth in vivo, decreased proliferation and apoptotic index in these cells. Development of apoptosis was characterized by the enhancement of the formation of reactive oxygen species and products of lipid peroxidation and was accompanied by a decrease in the activities of mitochondrial complexes I, III, and IV, and the release of cytochrome c and caspase 3-like activation of DNA fragmentation. Earlier, a similar apoptotic mechanism of antitumor activity has been shown for the flavonoid quercetin [99], Kamp et al. [100] suggested that the asbestos-induced apoptosis in alveolar epithelial cells was mediated by iron-derived oxygen species, although authors did not hypothesize about the nature of these species (hydroxyl radicals, hydrogen peroxide, or iron complexes ). 

Antioxidant activity of flavonoids has already been shown about 40 years ago [90,91]. (Early data on antioxidant flavonoid activity are cited in Ref. [92].) Flavonoids are polyphenols, and therefore, their antioxidant activity depends on the reactivity of hydroxyl substituents in hydrogen atom abstraction reactions. As in the case of vitamins E and C, the most studied (and most important) reactions are the reactions with peroxyl radicals [14], hydroxyl radicals [15], and superoxide [16]. 

It must be noted that the inhibitory effects of flavonoids and other antioxidants in nonhomogenous biological systems can depend not only on their reactivities in reactions with free radicals (the chain-breaking activities) but also on the interaction with biomembranes. Thus, Saija et al. [137] compared the antioxidant effects and the interaction with biomembranes of four flavonoids quercetin, hesperetin, naringen, and rutin in iron-induced... 

Although no good quantitative correlation between redox potentials of flavonoids and their prooxidant activities still was not documented, a relationship between the prooxidant toxicity of flavonoids to HL-60 cells and redox potentials apparently takes place [176]. However, there is a simple characteristic of possible prooxidant activity of flavonoids, which increases with an increase in reactive hydroxyl groups in the B ring. From this point of view, the prooxidant activity of flavonoids should increase in the range kaempferol < quercetin < myricetin (Figure 29.7). Thus, for many flavonoids the ratio of their antioxidant and prooxidant activities must depend on the competition between Reactions (14) and (15) and Reaction (17). 

A comparison with its different derivatives shows that 4 -OH is not a sole reactive group responsible for the antioxidant activity of resveratrol, while the trans-conformation is absolutely necessary for the inhibition of cell proliferation [187], However, similar to flavonoids resveratrol may exhibit prooxidant properties, for example to promote DNA fragmentation, although its prooxidant activity seems to be unimportant under physiological conditions [188],... 

Galati, G. et al., Glutathione-dependent generation of reactive oxygen species by the peroxidase-catalysed redox cycling of flavonoids, Chem. Res. Toxicol., 12, 521, 1999. 

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