Overcoming severe inflammatory conditions is quite important issue to prevent aging and aging-related diseases. Many papers have suggested multiple biological activities, including anti-inflammatory activity, of natural flavonoids in vitro and in vivo, whereas the molecular mechanisms, including the bioavailability and cellular accumulation, still remain unproven. Orally administered flavonoids are generally metabolized into their phase-II conjugates, glucuronides and sulfates, during absorption and tissue circulation. Therefore, understanding the molecular actions of the flavonoid conjugates underlying the health-beneficial activity may lead to the development of new strategies for the effective utilization of natural flavonoids in daily diet. We have recently found that quercetin-3-O-glucuronide (Q3GA), a major quercetin metabolite in human plasma, specifically accumulated in macrophages, followed by β-glucuronidase-catalyzed deconjugation into the biologically active aglycones. Thus, quercetin aglycone and/or its intracellular methylated derivatives exhibited signitifant anti-inflammatory effects, whereas Q3GA itself did not at all. Quercetin-3'-O-sulfate, another major quercetin conjugate in humans, was not deconjugated by macrophage-derived enzymatic activity and therefore scarcely exhibited the anti-inflammatory activity. These observations suggest that glucuronidated metabolites of flavonoids, rather than sulfated metabolites, could be the precursors, like prodrugs, of active aglycones in vivo. Phase-II conjugation of flavonoids is recognized as a competing pathway between glucuronidation and sulfation. Therefore, we are now investigating the protocols for quercetin intake that increase glucuronidation/sulfation ratio during absorption and metabolism of quercetin.

Anti-inflammatory mechanisms of dietary flavonoids linked with phase-II conjugation and macrophage-mediated metabolic conversions

256th National Meeting (2018)

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