Mechanism of Release of Ferritin Iron In Vivo by Xanthine Oxidase1

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Abstract
The release of ferritin iron in the liver to the plasma, after reduction by xanthine oxidase, has been confirmed in the intact animal for guinea pigs, rabbits and dogs. Administration of xanthine oxidase substrates or of nucleotides or nucleosides which can be converted to such substrates by the animal, leads to an increase in plasma iron. Inhibition studies in the presence of excess substrate indicate that the reduction of ferritin iron by reduced xanthine oxidase involves a site on the enzyme different from that which reacts with molecular oxygen or methylene blue. It is suggested that the site of ferritin iron reduction is associated with the nonheme iron of the enzyme and takes place by direct electron transfer. The implications of this biochemical mechanism for the release of storage iron from the liver in various physiological states are discussed. The physiological stimulus which is common to our experiments and which results in an accelerated release of iron from hepatic ferritin stores to the plasma is tissue hypoxia. This produces an increase in level of xanthine oxidase substrates and a consequent reduction and release of ferritin iron to the plasma. Since the result of lowered oxygen tension is a stimulation of erythrocyte synthesis, and therefore of iron incorporation into hemoglobin, the ferritin-xanthine oxidase system constitutes part of a homeostatic mechanism for the regulation of the level of iron in the circulation.