The Possible Significance of the Ferrous Oxidase Activity of Ceruloplasmin in Normal Human Serum

TLDR

Nonenzymic Fe(II) oxidation alone cannot explain the rate of Fe(III)-transferrin formation needed for hemoglobin synthesis and other iron-dependent processes. The study proposes that serum ceruloplasmin acts as a ferroxidase to accelerate transferrin iron saturation and stimulate iron utilization. Fe(II) oxidation was examined in serum at pH 7.35 across physiological oxygen concentrations. The data reveal a significant catalytic activity in serum, with ferroxidase activity correlating with p‑phenylenediamine oxidase, inhibited by azide and cyanide, diminished in low‑ceruloplasmin sera, associated with the ceruloplasmin fraction, and exhibiting zero‑order dependence on oxygen, supporting ceruloplasmin’s role as the serum ferroxidase.

Abstract

The oxidation of Fe(II) by serum was studied at pH 7.35 and at various oxygen concentrations which approach the physiological conditions of human serum. The nonenzymic oxidation of Fe(II) was estimated to be insufficient to account for a rate of Fe(III)-transferrin formation necessary to provide an adequate iron supply for hemoglobin and other biosyntheses if Fe(II) is a relevant source of serum iron. The results suggested that an appreciable catalytic activity was involved in Fe(II) oxidation in serum. The ferroxidase activity of various normal human sera correlates precisely with the p-phenylenediamine oxidase activity of these sera. This catalytic activity is inhibited by azide and cyanide, and is low in sera with reduced ceruloplasmin levels. Fe(II) oxidation is also associated with the ceruloplasmin fraction on diethylaminoethyl cellulose chromatography of serum. The oxidation of Fe(II) by ceruloplasmin is zero order with respect to oxygen (10 to 200 µm), whereas the nonenzymic oxidation is first order. A biological role for the ceruloplasmin of serum in promoting the rate of iron saturation of transferrin and in stimulating iron utilization and the designation of the enzyme as serum ferroxidase is proposed.