Thermodynamic parameters and mitochondrial effects of supramolecular complexes of quercetin with β-cyclodextrins

Abstract

The aim of the present study was to evaluate the thermodynamic parameters of the formation of supramolecular complexes of the flavonoid quercetin, a plant polyphenol with high therapeutic activity, and the molecular containers, β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD), as well as to assess the effects of quercetin and the quercetin - HPβСD complex on the functional activity of isolated rat liver mitochondria. The formation of the complex (stoichiometry 1:1) resulted in a marked elevation of quercetin water solubility: more than 5-fold in the case of 16 mM βCD (the association constant was equal to 300±45 М−1 as determined by the method of phase solubility diagram), and more than 50-fold in the case of 16 mM HPβCD (the association constant was equal to 3275±450 М−1), which reflects increased bioavailability of quercetin. In comparison, the association constant of the polyphenol sesamin - HPβСD complex formation (stoichiometry 1:1 and 1:2) was 2500 ± 350 М−1, and the solubility of sesamin in the complex increased more than 60-fold in the case of 10 mM HPβСD. The inclusion complex formation was spontaneous and exothermic, and both the enthalpic and entropic effects competed during complexation of polyphenol molecules with HPβCD, but the enthalpic factor was dominating in the bounding process in the case of quercetin and the entropic factor – in the case of sesamin. Quercetin and the quercetin - HPβCD complex considerably inhibited the respiratory activity of mitochondria, and uncoupled the oxidation and phosphorylation reactions, whereas quercetin alone, and not the complex, enhanced the mitochondria susceptibility to Ca2+-induced mitochondrial permeability transition (MPT). The complex quercetin - HPβCD (10–50 μM) was much more effective in preventing mitochondrial reduced glutathione depletion and α-ketoglutarate dehydrogenase impairment during mitochondria exposure to hypochlorous acid in comparison with the quercetin water solution due to enhanced availability of mitochondria matrix components to the antioxidant (quercetin). The decrease of quercetin lipophilicity after the complexation with HPβCD attenuated the effects on mitochondrial respiration and changed the direction of the effect on the MPT process owing to the quercetin redistribution between water and lipid phases.