Membrane lipids flavonoid interactions with

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. 

In addition, some flavonoids can differentially interact with membrane polar surfaces or penetrate into the bilayer, depending on certain characteristics of the reaction milieu. This is the case of quercetin, a flavonoid that at acidic pH is deeply embedded into planar lipid bilayers [Movileanu et al., 2000], while at... 

In summary, current evidence supports the interaction of flavonoids with membrane lipids. The associated perturbations in membrane physical properties can have a significant impact on membrane-associated processes. 

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. 

The final chapter, The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators by K. Michalak, O. Wesolowska, N. Motohashi and A. B. Hendrich, presents a very comprehensive review on important biological effects of phenothiazines and flavonoids due to interactions with membrane proteins and the lipid phase of membranes. The discussion includes the influence of these heterocycles on model and natural membranes, modulation of MDR transporters by these heterocycles, and the effects of these hetero cycles on ion channel properties. This review may attract much interest from medicinal and pharmaceutical chemists as well as heterocyclic chemists in the life science fields. 

Very recently, we reviewed the role of membrane action of flavonoids. The structure of flavonoids enables specific interactions with different membrane proteins (multidrug transporters, voltage-gated and chemically activated ion channels) and also nonspecific interactions with the lipid phase of membranes [8]. 

Chelating activity gives another possibility to flavonoids to interact with the oxidation of membrane lipids, and it is considered important for... 

Fig. 6.2 Interactions between phospholipids, membrane proteins, and flavonoids. (a) In acidic and neutral conditions, flavonoids such as quercetin intercalate between phospholipids in the hydrophobic zone and initiate the formation of an ordered lipid phase. Flavonoids can also interact with membrane proteins, (b) In alkaline conditions, deprotonated flavonoids cover the polar head surface of phospholipids and interact with membrane proteins, (c) When phloretin replaces quercetin, the distance between the hydrocarbon chains is increased and lipids form a superordered lipid phase. Intercalation of phloretin between the polar heads of phospholipids induces micelle formation, (d) Outer and inner phospholipidic layers can be interdigitated when phospholipids are spaced by phloretin but not by quercetin (a and b). Modified from Tarahovsky et al. (2008).

Immobilized artificial membrane (lAM) stationary phase consists of a monolayer of phospholipid covalently immobilized on an inert silica support. The lAM stationary phase mimics the lipid environment found in cell membranes, and it can be used for elucidating drug-membrane interactions. The interaction of catechins, flavones, flavonols, anthocyanidins, and anthocyanins with phosphatidylcholine was investigated by HPLC with an lAM colunm. The lAM partition coefficients of the flavonoids correlated well with the amounts flavonoids incorporation into the liposomes [42]. 

Quercetin displays potent antithrombotic effects It inhibits thrombin and ADP-induced platelet aggregation in vitro, and this may be through inhibition of phospholipase C activity rather than through inhibition of thromboxane synthesis. Flavo-noid binding to platelet membranes may inhibit the interaction of activated platelets with vascular endothelium. In addition, quercetin elicits coronary vasorelaxation that is endothelium independent. The antioxidant activity of flavonoids may also prevent the damaging action of lipid peroxides generated by activated platelets on endothelial nitric oxide and prostacyclin, which both inhibit platelet aggregation and have vasodilatory activity. 

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