The toxicities of native and modified hemoglobins

Recent research on the potential use of hemoglobin derivatives as a blood substitute has revealed that the administration of large quantities of free hemoglobin into the circulation results in a variety of toxic side effects. Because it has been well established that hemoglobin, like myoglobin, has considerable pro-oxidant activity, a number of studies have appeared suggesting that the administered hemoglobins may catalyze various oxidative and peroxidative reactions, which in turn, would cause the observed pathologic conditions. This occurs as a result of the in vivo formation of highly oxidized forms of the native and modified hemoglobins. In addition, it has been proposed that considerable amounts of free hemin and iron may be generated as a result of the catabolism of the injected hemoglobin. Hemin is known to be very toxic when present in large amounts, and iron could catalyze the formation of hydroxyl radicals via Fenton-type reactions. Thus, the toxic activities of catabolic products of hemoglobin could also be involved in all or part of the observed side effects. The purpose of this review is to consider the conditions under which reactive species of hemoglobin may be formed in vivo, their potential reactivity, and whether their individual or combined oxidative activities could account for the biological damage that is observed in vivo following hemoglobin transfusions.