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The current chelation therapy has several drawbacks, including lack of selectivity, which could lead to trace metal depletion. Consequently, the proper function of metalloenzymes can be disrupted. Flavonoids possess chelating properties and hence interfere with the homeostasis of essential metals. We focused on zinc, an important trace metal required for the function of many enzymes and transcription factors. After making an initial evaluation of the Zn2+-chelating properties of a series of flavonoids, the effect of these compounds on various zinc-containing enzymes was also investigated. We performed enzyme inhibition assays spectrophotometrically using yeast and equine alcohol dehydrogenases and bovine glutamate dehydrogenase. Nine of the 21 flavonoids tested were capable of chelating Zn2+. Baicalein and 3-hydroxyflavone were the most potent Zn2+chelators under slightly acidic and neutral pH conditions. This chelation was also confirmed by the ability to reverse Zn2+-induced enzymatic inhibition of bovine glutamate dehydrogenase. Although some flavonoids were also able to inhibit zinc-containing alcohol dehydrogenases, this inhibition was likely not caused by Zn2+chelation. Luteolin was a relatively potent inhibitor of these enzymes regardless of the presence of Zn2+. Docking studies confirmed the binding of active flavonoids to equine alcohol dehydrogenase without any significant interaction with the catalytic zinc.

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.