Characterization and structure-activity relationship of natural flavonoids as hERG K(+) channel modulators.

OBJECTIVES: Flavonoids are present in varying concentrations in plant foods and have been reported to have numerous pharmacological activities, such as anti-cancer, antioxidant, anti-inflammatory, hepatoprotective, and vasodilator effects. We found that quercetin, fisetin, and some related flavonoid derivatives could inhibit human ether-à-go-go-related gene (hERG) K(+) channels.

KEY FINDINGS: In this study, we tested the effects of a series of flavonoids on the hERG K(+) channel expressed in HEK293 cells. For the first time, we demonstrate that quercetin and fisetin (Fise) are potent hERG current blockers. The 50% inhibiting concentration (IC50) and maximum efficacy (Emax) of quercetin were 11.8±0.9μM and 82±2%, while those of fisetin were 38.4±6μM and 100±6%, respectively. Luteolin (Lute) was a less potent inhibitor of hERG current (48±1% at 100μM). Galangin, kaempferol, and isorhamnetin (100μM) showed weaker activity on the hERG currents.

CONCLUSION: These results suggest that quercetin, fisetin, and luteolin are potent hERG K(+) channel inhibitors and reveal the structure-activity relationship of natural flavonoids.