An essential difference in the reactivity of the glutathione adducts of the structurally closely related flavonoids monoHER and quercetin

During the scavenging of free radicals flavonoids are oxidized to electrophilic quinones. Glutathione (GSH) can trap these quinones, thereby forming GSH–flavonoid adducts. The aim of this study was to compare the stability of the GSH–flavonoid adduct of 7-mono-O-(β-hydroxyethyl)rutoside (monoHER) with that of quercetin. It was found that GSH–quercetin reacts with the thiol N-acetyl-l-cysteine (NAC) to form NAC–quercetin, whereas GSH–monoHER does not react with NAC. In addition, the adduct of the monoHER quinone with the dithiol dithiothreitol (DTT) is relatively stable, whereas the DTT–quercetin adduct is readily converted into quercetin and DTT disulfide. These differences in reactivity of the thiol–flavonoid adducts demonstrate that GSH–monoHER is much more stable than GSH–quercetin. This difference in reactivity was corroborated by molecular quantum chemical calculations. Thus, although both flavonoid quinones are rapidly scavenged by GSH, the advantage of monoHER is that it forms a stable conjugate with GSH, thereby preventing a possible spread of toxicity. These findings demonstrate that even structurally comparable flavonoids behave differently, which will be reflected in the biological effects of these flavonoids.

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► We compare the reactivity of the glutathione (GSH) adducts of two flavonoids.
► MonoHER-quinone forms a stable adduct with GSH.
► Quercetin-quinone forms a reversible adduct with GSH.
► The reversibility of GSH-quercetin may spread toxicity.
► The stability of GSH-monoHER prevents this spread of toxicity.