Radical producing and consuming reactions of hemoglobin: how can we limit toxicity?

Hemoglobin has a range of enzymatic activities that can affect its putative pharmacological role as an extracellular oxygen carrier. In the presence of peroxides, deoxyhemoglobin and methemoglobin can produce free radicals and induce lipid peroxidation. Oxyhemoglobin can oxidize the free radical nitric oxide to nitrate, yet deoxyhemoglobin can produce nitric oxide from nitrite. These enzymatic reactions can induce or diminish toxic side reactions when hemoglobin is added in vivo. For example the removal of the free radical vasodilator nitric oxide, or the addition of the lipid-derived vasoconstrictor F2-isoprostane, will both alter blood flow and blood pressure. In order to determine the dominant effects it is necessary to design molecules with differing radical reactivities. Molecules have been designed with these modifications and this article will review their role in determining mechanism as well as their possible functionality as blood substitutes.