Iron Metabolism, Calcium, Magnesium and Trace Elements: A Review

Abstract

Iron (Fe) is fundamental to life on earth. In the human body, it is both essential and harmful if above threshold. A similar balance applies to other elements: calcium (Ca), magnesium (Mg), and trace elements including copper (Cu), zinc (Zn), lead (Pb), cadmium (Cd), mercury (Hg), and nickel (Ni). These elements share some proteins involved in the absorption and transport of Fe. Cu and Cd can inhibit Fe absorption, while excess of Fe may antagonize Cu metabolism and reduce ceruloplasmin (Cp). Excessive Fe can hinder Zn absorption and transferrin (Trf) can bind to both Zn and Ni. Ca is able to inhibit the divalent metal transporter 1 (DMT1) in a dose-dependent manner to reduce Fe absorption and low Mg concentrations can exacerbate Fe deficiency. Pb competitively inhibits Fe distribution and elevated Cd absorption reduces Fe uptake. Exposure to Hg is associated with higher ferritin concentrations and Ni alters intracellular Fe metabolism. Fe removal by phlebotomy in hemochromatosis patients has shown to increase the levels of Cd and Pb and alter the concentrations of trace elements in some types of anemia. Yet, the effects of chronic exposure of most trace elements remain poorly understood.

Fig. 1

The absorption process of iron (Fe) at the enterocyte level. Heme-Fe is absorbed via the hem carrier protein 1 (HCP-1), while non-heme Fe is absorbed through the divalent metal transporter 1 (DMT1) after conversion of Fe³⁺ to Fe²⁺ by duodenal cytochrome B (DCYTB). Fe can either be stored in ferritin or exported into the bloodstream by ferroportin (FPN1), the sole known Fe-exporter, which is regulated by Hepcidin (Hep) through downregulation. Hephaestin and ceruloplasmin (Cp) facilitate the oxidation of Fe²⁺ to Fe³⁺ for binding to transferrin (Trf). Cells dependent on Fe have transferrin receptors on their surface, allowing them to uptake Fe from Trf. Cp also binds copper (Cu) and transports it to cells. Cu enters the enterocyte via the Copper transporter 1 (CRT1). Magnesium (Mg) and calcium (Ca) enter the enterocyte through specific transporters (TRPM6 and TRPV6), and both elements are exported into the blood through ATP-ase activity. Zinc (Zn) is imported via ZIP transporter(s), while efflux is via Zn transporter (ZnT) (created with BioRender.com)