Hydrophobic flavonoids

Similar to hydrophilic flavonoids, hydrophobic flavonoids can affect membrane permeability. Alterations in this biophysical property of liposome bilayers lead to the release of bulky molecules entrapped into the inner aqueous space. As mentioned in the previous section, a strong correlation was found between flavonoid retention to a hydrophobic matrix and their capacity to induce membrane leakage [Ollila et al., 2002]. Interestingly, hydrophilic flavonoids, such as (—)-epicatechin and related procyanidins (dimer to hex-amer) prevented Fe2 + -mediated liposome permeabilization, although in this case the beneficial effect could be related to both their antioxidant and metal chelating capacities and their membrane stabilizing properties [Verstraeten et al., 2004],... 

The finding that water-soluble flavonoids could exert their beneficial properties at the hydrophobic portion of the membrane was also observed in in vivo studies and in cells in culture. For example, erythrocytes obtained from animals fed a flavanol- and procyanidin-rich meal showed reduced susceptibility to free-radical-mediated hemolysis [Zhu et al., 2002]. Consistently, we demonstrated that procyanidin hexamers, which interact with membranes but would not be internalized, protected Caco-2 cells from AMVN- and bile-induced oxidation [Erlejman et al., 2006]. When liposomes were preincubated with a series of flavonoids with diverse hydrophobicity, not only hydrophobic flavonoids prevented AMVN-mediated lipid oxidation but also the more hydrophilic ones [Erlejman et al., 2004]. Similarly to what was previously found in liposomes, the protective effects of flavonoids against AMVN-supported oxidation was strongly associated with their capacity to prevent membrane disruption by detergents, supporting the hypothesis of a physical protection of membranes by preventing oxidants to reach fatty acids. 

A different mechanism should account for the antioxidant ability of hydrophobic flavonoids, which can be incorporated into the bilayer where they can affect certain membrane physical properties. It is well-known that alterations in membrane rheology will affect the extension and rate of lipid oxidation. For example, increased lipid oxidation rates have been observed... 

How can we keep our health against these reactive oxygen radicals Fortunately, vitamin C (hydrophilic), vitamin E (hydrophobic), flavonoids, and other polyphenols can function as anti-oxidants. These anti-oxidants are phenol derivatives. Phenol is a good hydrogen donor to trap the radical species and inhibits radical chain reactions. The formed phenoxyl radical is actually stabilized by the resonance effect as shown in eq. 1.8. Thus, phenol and polyphenol derivatives are excellent hydrogen donors to inhibit the radical reactions and, therefore, they are called radical inhibitors. 

Flavones consist chiefly of glycosides of luteolin, chrysin, and apigenin. They are less common in fruits [8]. Polymethoxylated flavones, the most hydrophobic flavonoids, present in citrus fruits (mainly in the peel, the nonedible part of the fruit) are tangeretin and nobiletin. Apigenin and chrysin possess anti-inflammatory and free-radical scavenging properties in several cancer cell lines and inhibit tumor cell invasion, metastasis, and mitogen-activated protein kinases (MAPK) and their downstream oncogenes [26]. 

Acylations of carbohydrate derivatives such as alkyl glucosides and galactosides have also been successfully performed in ionic liquids [63]. Similarly, the flavonoid glycosides naringin and rutin were acylated with vinyl butyrate in ionic liquid media in the presence of a number of lipases, e.g., CaLB (Novozym 435), immobilized TIL, and RmL [119]. The products are of interest for application as strong antioxidants in hydrophobic media. 

Flavonoids and other polyphenols can interact with lipids and proteins. The interactions with proteins could be both unspecific or specific, meanwhile the interactions with lipids seems to be rather unspecific, based essentially on physical adsorption. This physical adsorption would mostly depend on the hydrophobic/hydrophilic characteristics of the flavonoid molecule, the number of hydroxyl substituents, and the polymerization degree [Erlejman et al., 2004 Verstraeten et al., 2005, 2003, 2004]. 

Flavonoids bear different degrees of hydroxylation, polymerization, and methylation that define both specific and nonspecific interactions with membrane lipids. Molecule size, tridimensional structure, and hydrophili-city/hydrophobicity are chemical parameters that determine the nature and extent of flavonoid interactions with lipid bilayers. The hydrophilic character of certain flavonoids and their oligomers endows these molecules with the ability to bind to the polar headgroups of lipids localized at the water-lipid interface of membranes. On the other hand, flavonoids with hydrophobic character can reach and cross the lipid bilayer. In this section, we will discuss current experimental evidences on the consequences of flavonoid interactions with both the surface and the hydrophobic core of the lipid bilayer. 

As previously mentioned, certain flavonoids can penetrate into the hydrophobic core of membranes, a feature that mainly relies on their hydrophobic character, which is dictated by flavanoid chemical structure and spatial conformation. When flavonoid hydrophobicity was assessed from the partition coefficient between ra-octanol and an aqueous solution, the following order of hydrophobicity was observed flavone, genistein > eriodictyol, myricetin, quercetin, kaempferol, hesperetin, daidzein > > galangin, morin, flavanone, naringenin, taxifolin (Table 4.1). 

Besides their free-radical trapping properties, flavonoids can interfere with the capacity of oxidants to reach the bilayer. A study from our laboratory demonstrated that the adsorption of water-soluble ( )-epicatechin oligomers (dimer to hexamer) to membranes prevents lipid oxidation initiated by the azocompound 2,2 -azobis (2,4-dimethylvaleronitrile), (AMVN), a hydrophobic molecule that upon its incorporation into the bilayer decomposes yielding peroxyl radicals [Verstraeten et al., 2003], In this case, given that the oxidant... 

The affinity of flavonoids for phospholipid membranes has been unequivocally demonstrated by many authors. Many biological functions of these compounds are also believed to be the result of flavonoid interactions with cell membranes. Partition coefficients for a large group of flavonoids between water and olive oil were determined, and it was shown that the hydrophobic-ity of the compounds is inversely proportional to the number of OH groups. 

Additionally, it was noticed that flavones were slightly more hydrophobic than flavanones possessing the same number of hydroxyl groups [103]. Flavonols turned out to be the least hydrophobic from all the compounds studied. The degree of DPH fluorescence quenching in PC liposomes by flavonoids was used as a measure of the relative membrane affinity of these... 

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