Open AccessMechanisms of Toxicity and Modulation of Hemoglobin-based Oxygen Carriers
Author(s) -
Abdu I. Alayash
Publication year - 2019
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/shk.0000000000001044
Subject(s) - chemistry , hemoglobin , toxicity , heme , nitric oxide , oxidative phosphorylation , pharmacology , allosteric regulation , methemoglobin , oxygen , oxygen transport , biochemistry , enzyme , medicine , organic chemistry
Several adverse events have been associated with the infusion of hemoglobin-based oxygen carriers (HBOCs), including transient hypertension, gastrointestinal, pancreatic/liver enzyme elevation, and cardiac/renal injury in humans. Although several mechanisms have been suggested, the basis of HBOC toxicity is still poorly understood. Scavenging of vascular endothelial nitric oxide (NO) and heme-mediated oxidative side reactions are thought to be the major causes of toxicity. However, based on more recent preclinical studies, oxidative pathways (driven by the heme prosthetic group) seem to play a more prominent role in the overall toxicity of free Hb or HBOCs. HBOCs display a diversity of physicochemical properties, including molecular size/cross-linking characteristics leading to differences in oxygen affinity, allosteric, redox properties, and even oxidative inactivation by protein/heme clearing mechanisms. These diverse characteristics can therefore be manipulated independently, leaving open the possibility of engineering a safe and effective HBOC. To date, several antioxidative strategies have been proposed to counteract the redox side reactions of current generation HBOCs.