Oxidation of hemoglobin: mechanisms of control in vitro and in vivo

Abstract

SUMMARY Hemoglobin (Hb) within red blood cells (RBC) is protected from oxidative processes by enzymatic and small molecule antioxidants as well as the RBC membrane that provides a physical barrier against oxidation. When Hb is introduced into the circulation as a result of hemolysis or following infusion of Hb-based oxygen carriers (HBOCs; ‘blood substitutes’), the control of oxidative processes becomes dependent on plasma oxidative status. In vitro studies clearly demonstrate that Hb and HBOCs undergo oxidative modification at the site of heme iron and at multiple amino acid sites as a result of autoxidation, nitrosylation and peroxidation. Recent findings from in vitro studies provide a strong basis for understanding of potential toxicity in vivo. The antioxidative status of both plasma and tissue becomes an important factor in the control of Hb and HBOC oxidation and nitrosylation in the circulation. Several studies that performed ex vivo and in vivo have demonstrated a critical role for plasma antioxidants such as ascorbic acid and uric acid in maintaining Hb and HBOCs in functional non-oxidized states. In the present review we discuss mechanisms of Hb and HBOC autoxidation, nitrosylation and peroxidation in vitro and in vivo. Additionally, we explore the role(s) of plasma antioxidants in maintaining functional HBOC status that may potentially be exploited as part of protective strategies against Hb and HBOC oxidative toxicity.