Quercetin,
a common flavonoid from human diet, is extensively metabolized.
Its two metabolites with the preserved flavonoid core were tested
in detail for their interactions with transition metals, iron and
copper. Both compounds chelated both metals; however, there were some
significant differences between them notwithstanding that the major
chelation site (3-hydroxy-4-keto) was the same. The complex stoichiometries
were also determined under different pH conditions and in both oxidation
states. Mostly, complexes 2:1, flavonoid to metal, were observed.
Both compounds reduced iron and copper in a bell-shaped manner with
tamarixetin being less potent in general. Both metabolites potentiated
the Fenton reaction triggered by iron, while they were able to decrease
the copper-based Fenton reaction under acidic conditions. In cellular
experiments, both metabolites attenuated the copper-triggered hemolysis
with isorhamnetin being more potent. In conclusion, there are differences
between methylated metabolites of quercetin in relation to their interactions
with biologically relevant transition metals.
Human serum albumin (HSA) is the most abundant plasma protein in circulation. The three most important drug-binding sites on HSA are Sudlow’s Site I (subdomain IIA), Sudlow’s Site II (subdomain IIIA), and Heme site (subdomain IB). Heme site and Site I are allosterically coupled; therefore, their ligands may be able to allosterically modulate the binding affinity of each other. In this study, the effects of four Heme site ligands (bilirubin, biliverdin, hemin, and methyl orange) on the interaction of the Site I ligand warfarin with HSA were tested, employing fluorescence spectroscopic, ultrafiltration, and ultracentrifugation studies. Our major results/conclusions are the following. (1) Quenching studies indicated no relevant interaction, while the other fluorescent model used suggested that each Heme site ligand strongly decreases the albumin binding of warfarin. (2) Ultrafiltration and ultracentrifugation studies demonstrated the complex modulation of warfarin–HSA interaction by the different Heme site markers; for example, bilirubin strongly decreased while methyl orange considerably increased the bound fraction of warfarin. (3) Fluorescence spectroscopic studies showed misleading results in these diligand–albumin interactions. (4) Different Heme site ligands can increase or decrease the albumin binding of warfarin and the outcome can even be concentration dependent (e.g., biliverdin and hemin).
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