The Effect of Methemoglobin on the Equilibrium Between Oxygen and Hemoglobin

Abstract

Methemoglobin mav be formed from hemoglobin in vitro bv a wide range of oxidizing agents. Such compounds also act in vivo if they ian permeate the red cell membrane; other substances such as aniline and &its derivatives (including the sulfanilimide series) are ineffective with hemoglobin solutions but do form methemoglobin in vivo, possibly because they give rise, in the course of their metabolism, to intermediate compounds with oxidizing properties, e.g., aminophenol or phenylhydroxylamine. Methemoglobinemia is accordingly a fairly common condition both in chemical indust$ries and in drug therapy (for reviews v. Peters and Van Slyke, 19 ; Wendel, 22). The symptoms are very similar to those produced by an equivalent degree of CO-hemoglobinemia, (see especially (14)) the toxic effects in both cases being much greater than those produced by the same amount of anemia. Some further action besides the lowering of the O2 carrying power of the blood is therefore indicated. In the case of methemoglobinemia this has been thought to be due entirely to the direct effect of the methemoglobin producing agent on the tissues, e.g., vasodilatation in the case of nitrites. Carbon monoxide, however, does not act directly on the tissues except at pressures much higher than those usually found in CO poisoning, and its extra effect has been explained in another way. Douglas, Haldane and Haldane (12) (see also Stadie and Martin, 20) observed that when part of the hemoglobin in blood is combined with CO, the oxygen dissociation curve of the remaining hemoglobin is shifted to the left and is less S-shaped. This "affinity effect" greatly hinders the unloading of 02 from the blood to the tissues and in Haldane's view (13) accounts for the fact that "miners may be doing their ordinary work though their hemoglobin percentage is reduced to half or less by ankylostomiasis. .. whereas a person whose blood is half saturated with CO is practicallv helpless." These findings with CO hemoglobin made us ask whether methemoglobin might not have a similar effect on the dissociation curve of oxyhemoglobin. From a theoretical standpoint this is a reasonable question, since methemoglobin has long since ceased to be regarded as an irreversible compound: Conant and his colleagues (7, 8) have indeed shown that the same equilibrium point) is reached between CO-hemoglobin, methemoglobin, CO, ferricyanide and ferrocyanide from whichever side the equilibrium is approached. A-similar reversible equilibrium was also demonst$rated in the presence of 02 in place of CO. Now since Haldane's work has proved that in the reversible system CO hemoglobinoxyhemoglobin-hemoglobin-CO-Oz, the presence of CO and COHb affects the equilibrium between 02 and hemoglobin (and similarly the presence of 02 56

Oxygen Affinity of Hemoglobins F and A Partially Oxidized to Methemoglobin: Influence of 2,3-Diphosphoglycerate

“…It is well known that the oxygen affinity of partially oxidized HbA is increased (8,10). However, this pronounced left shift of the hemoglobin oxygen equilibrium curve with increasing fractions of met-Hb in vitro was not observed in patients with sustained methemoglobinemia (for references see the reviews of Jaff6 and Hsieh (14) and Kiese (17)).…”

Cyclophosphamide-induced methemoglobinemia

“…In addition, the oxygen affinity of residual ferrous hemes is increased, resulting in shifting of the oxygen dissociation curve to the left. 2 Methemoglobinemia may arise as a result of a genetic defect in red blood cell metabolism or hemoglobin structure, or it may be acquired following exposure to various oxidant drugs or toxins. 3 Symptoms from methemoglobinemia vary according to the level of MetHb and underlying medical problems, especially in patients with lung disease.…”

The Acute Toxicity of Nitrite Inhalants

“…The administration of nitrites by any route can produce profound methemoglobinemia. Tissue anoxemia can result from methemoglobinemia (Darling and Roughton 1942;Lester and Greenburg 1944). Ascorbic acid and methylene blue may be effective prophylactic agents for nitrite poisoning if administered promptly, but laboratory studies offer little support for this in the case of isobutyl nitrite ingestion (McFadden and Maickel 1982).…”