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Introduction: Multicopper ferroxidases (MCFs) are proteins important for intestinal iron absorption and iron recycling. MCFs are hypothesized to oxidize ferrous iron from the iron exporter Ferroportin so that the iron can bind to circulating Transferrin. There are three known MCFs expressed in vertebrates: Ceruloplasmin (CP), Hephaestin (HP), and the recently discovered Zyklopen (ZP). In order to determine the individual and overlapping roles of the MCFs, we generated mouse models with single, double, and triple MCF knockout. Methods: We used the cre-lox system to create HP and ZP knockouts and then crossed these mice with each other and with CP knockout mice to generate double and triple knockouts. The general phenotype, hematology, tissue iron levels, and the absorption and distribution of radiolabeled iron were then studied. Results: Mice lacking HP and/or CP exhibited clear defects in iron metabolism, with double knockout leading to a severe anemia and fatality at 23-30 weeks of age. Mice with knockou...

It has been assumed for some time that the main Cu-containing proteins in blood plasma are ceruloplasmin (Cp), albumin and transcuprein/a2-macroglobulin, Cp being the main ferroxidase (Fx) implicated in mediating efflux of iron from certain cells. Recent studies in our laboratory suggest the picture is much more complex, and that other known and unknown factors containing Cu are still to be identified. We had previously shown in mice that knocking out Cp only knocked down plasma Fx activity by half. We now have evidence that knocking out hephaestin (Hp) a membrane-tethered Cp-homologue reduces plasma Fx activity and a peak in the Cu profile obtained by size exclusion chromatography (SEC), indicating that solubilized Hp may be entering the circulation. Also, a patient with twice normal level of plasma Cu but Cp protein in the normal range had twice normal levels of Fx activity, suggesting that ratios of holo to apo-Cp were elevated or that another Fx increased in response to the contraceptives. Use of the ...