Interaction of Quercetin, Cyanidin, and Their O-Glucosides with Planar Lipid Models: Implications for Their Biological Effects

Abstract

Flavonoids are specialized metabolites produced by plants, as free aglycones or as glycosylated derivatives, which are particularly endowed with a variety of beneficial health properties. The antioxidant, anti-inflammatory, antimicrobial, anticancer, antifungal, antiviral, anti-Alzheimer's, anti-obesity, antidiabetic, and antihypertensive effects of flavonoids are now known. These bioactive phytochemicals have been shown to act on different molecular targets in cells including the plasma membrane. Due to their polyhydroxylated structure, lipophilicity, and planar conformation, they can either bind at the bilayer interface or interact with the hydrophobic fatty acid tails of the membrane. The interaction of quercetin, cyanidin, and their O-glucosides with planar lipid membranes (PLMs) similar in composition to those of the intestine was monitored using an electrophysiological approach. The obtained results show that the tested flavonoids interact with PLM and form conductive units. The modality of interaction with the lipids of the bilayer and the alteration of the biophysical parameters of PLMs induced by the tested substances provided information on their location in the membrane, helping to elucidate the mechanism of action which underlies some pharmacological properties of flavonoids. To our knowledge, the interaction of quercetin, cyanidin, and their O-glucosides with PLM surrogates of the intestinal membrane has never been previously monitored.

Keywords: antioxidant; conductive unit; cyanidin; cyanidin-3-O-glucoside; interface active compounds; planar lipid membrane; polyphenols; quercetin; quercetin-4′-O-glucoside.

Figure 1

Chemical structures of the four flavonoids used in our study.

Figure 2

Quercetin, cyanidin, and their O-glucosides’ channel-like activity in DOPS:DOPE:POPC PLMs. Example of chart recordings of channel-like activity of quercetin (A), quercetin-4′-O-glucoside (B), cyanidin (C), and cyanidin-3-O-glucoside (D) in PLMs made up of DOPS:DOPE:POPC with associated histograms of the conductance fluctuations. The histograms of the probability, P(Λ), for the frequency of a given conductivity unit were fitted by a Gaussian distribution, which is shown as a solid curve. Experiments were performed in the presence of the different compounds (0.02 mg/mL) added to the cis side, while the aqueous phase contained 1 M KCl (pH 7) and T = 23 ± 1 °C. Applied voltage was set to 40 mV.

Figure 3

Biophysical and statistic parameters of four flavonoids’ channel-like events in DOPS:DOPE:POPC PLM. (a) The mean conductance (Λ_c ± SE) and (b) frequency (F ± SD) of four flavonoids’ channel-like events at different applied voltages. The minimum and maximum number of channel-like events considered (N) out of a total number of channel-like events considered (Nt) was: Quercetin = 167 < N < 772, Nt = 3599; Quercetin-4′-O-glucoside = 155 < N < 786; Nt = 3187; Cyanidin = 228 < N < 616, Nt = 2895; Cyanidin-3-O-glucoside = 122 < N < 528, Nt = 1718.

Figure 4

Schematic model of the four flavonoids’ interaction with DOPS:DOPE:POPC PLM. Quercetin-4′-O-glucoside and cyanidin-3-O-glucoside adsorb onto the membrane surface (top), while quercetin and cyanidin localize at the interface between the polar region of head groups and the hydrophobic core of the bilayer (bottom). The incorporation of the four flavonoids into the membrane and the formation of conductive units influences the electrical properties of PLM.