Differences in pharmacological activities of the antioxidant flavonoid monoher in humans and mice are caused by variations in its metabolic profile

Despite its well-known cardiotoxicity, the anthracycline doxorubicin continues to be a widely used chemotherapeutic agent. The flavonoid 7-mono-O-(beta-hydroxyethyl)-rutoside (monoHER) has shown protection against doxorubicin-induced cardiotoxicity in mice. However, this protection has not been observed in humans. This prompted us to investigate monoHER metabolism in humans and compare it with that in mice. Five healthy volunteers received monoHER by intravenous infusion. After infusion, bile fluid was collected, and the monoHER metabolites were identified by liquid chromatography-diode-array detection (LC-DAD), time-of-flight mass spectrometry (TOF-MS), and (1)H-nuclear magnetic resonance (NMR). Thirteen different metabolites were identified. MonoHER was predominantly converted into inactive glucuronidated metabolites. In mice, the major metabolic route is methylation, which forms bioactive metabolites that are implicated in the cardioprotective effect of monoHER. This indicates that the different pharmacological effects of monoHER in mice and humans might be explained by a difference in monoHER metabolism. This study adds to the growing appreciation of flavonoid metabolites as bioactive compounds.