Is iron sufficiency a risk factor in ischemic heart disease?

T he discovery of superoxide dismutasel provided a highly specific probe for the implication of the superoxide free radical (O2) in numerous biological processes. From the beginning, though, there were those who were disquieted by the rather robust nature of the damage that was apparently inflicted by this relatively mild-mannered radical. Soon, evidence suggested that superoxide radical was not acting alone but was, in fact, collaborating with hydrogen peroxide (the product of its dismuta-tion) to produce a species with much greater oxidiz-See p 1006 ing potential than either of the coconspirators.2 This new species was presumed to be the hydroxyl radical (OH.), generated by a reaction first proposed in 1934 by Haber and Weiss3: 02 +H2O2->2+H-+OH+ (1) This suggestion, too, left some uneasy. Weinstein and Bielski4 reported the rate constant for this reaction to be so slow as to preclude biological relevance. Iron, however, was found to catalyze the reactions56: O2_ +Fef3-O2+Fe+2 (2) Fe+2+H202-Fe+3+OH-+OH. (1) This combination of reactions is now commonly referred to as the "iron-catalyzed Haber-Weiss reac-tion" or as "superoxide-driven Fenton chemistry," as Reaction 3 had been proposed much earlier by Fenton.7 It would seem proper as well to refer to it simply as Haber-Weiss chemistry, because these investigators postulated all three reactions.3 The question of mechanism does not end there. Although nearly everyone agrees that the interaction of superoxide, iron, and hydrogen peroxide generates a potent oxidant, not everyone agrees that the species The opinions expressed in this editorial comment are not necessarily those of the editors or of the American Heart Association. is the hydroxyl radical. In some systems, the reactivity of the oxidant differs from that of radiolytically generated hydroxyl radical.89 Koppenol8 has suggested that Reaction 3 may alternatively be written as follows: Fe+2+H202->FeO° +H2O (4) The ferryl ion (FeO+2) has oxidant properties similar to, but somewhat less potent than, hydroxyl radical. From a physiological or clinical perspective, the important point to appreciate is that iron may seriously exacerbate any oxidative stress. Of interest, higher organisms are particularly careful about how iron is handled. There is never any "free" or loosely chelated iron in the healthy state. It is transported in the ferric state, bound to transferrin, in a complex that is especially difficult to reduce. Likewise, it is stored in the ferric state by ferritin, a protein found in nearly all tissues and in plasma. Importantly, the superoxide radical is capable of reducing ferritin-bound …