An in Vivo Factor Connecting Sustained Reactive Oxygen Species Capture with Rapid Disposition: Quercetin Distribution into Hemoglobin

Abstract

The in vivo antioxidant effects of freely available quercetin (Qc) on human health are poorly defined by Qc pharmacokinetics, with high binding capacity to plasma albumin, wide distribution, and a short half-life. To pharmacokinetically investigate reactive oxygen species (ROS)-scavenging pathways of Qc, we focused on in vivo upstream factors (splenic macrophage-generated ROS and deformed erythrocytes) of mouse acetaminophen (APAP)-induced liver damage. Qc co-treatment rescued the hepatic accumulation of blood cells and deformed blood cells without affecting APAP metabolite–blood cell adduct levels. It clearly reduced lipid hydroperoxidation of blood cells after APAP overdose, suggesting in vivo protective effects against splenic ROS attack. Our in vitro data with Qc derivatives showed that the 3-, 3′-, and 4′-OH groups in the Qc molecule participated in formation of the Qc–blood cell complex. 5-Hydroxyl-lacking fisetin competitively bound to Qc-binding site(s) in the mouse hemoglobin (Hb) protein molecule. When Qc was injected into mice, crude Hb strongly interacted with Qc even after 3 h, differing from rapid Qc disposition within 30 min from plasma. The Qc–Hb interaction suggested a source of the short half-life and wide distribution of Qc. Therefore, we suggest that rapid formation of the Qc–Hb protein complex is essential in determining an in vivo upstream factor connecting in vivo ROS-scavenging effects with Qc disposition. When Qc is intravenously and orally administered, the Qc–Hb protein complex rather than Qc in plasma is an important factor in analyzing Qc pharmacokinetics, leading to determination of intake safely available for human healthcare and re-evaluation of the poor Qc bioavailability reported.