Quercetin Oxidation Paradoxically Enhances its Antioxidant and Cytoprotective Properties

Quercetin oxidation is generally believed to ultimately result in the loss of its antioxidant properties. To test this assertion, quercetin oxidation was induced, and after each of its major metabolites was identified and isolated by HPLC-DAD-ESI-MS/MS, the antioxidant (dichlorodihydrofluorescein oxidation-inhibiting) and cytoprotective (LDH leakage-preventing) properties were evaluated in Hs68 and Caco2 cells exposed to indomethacin. Compared to quercetin, the whole mixture of metabolites (Q(OX)) displayed a 20-fold greater potency. After resolution of Q(OX) into 12 major peaks, only one (peak 8), identified as 2,5,7,3 ',4 '-pentahydroxy-3,4-flavandione or its 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone tautomer, could account for the antioxidant and cytoprotective effects afforded Q(OX). Peak 8 exerted such effects at a 50 nM concentration, revealing a potency 200-fold higher than that of quercetin. The effects of peak 8 were seen regardless of whether it was added to the cells 40 min before or simultaneously with the oxygen-reactive species-generating agent, suggesting an intracellular ability to trigger early antioxidant responses. Thus, the present study is the first to reveal that in regard to the intracellular actions of quercetin, attention should be extended toward some of its oxidation products.