Iron and Zinc Homeostasis

Iron is the most abundant element on Earth. Despite this it is the most common micronutrient deficiency on Earth with up to 50% of all children under 5 years and pregnant women in developing countries affected. The ability of iron to both bind oxygen and to donate and accept electrons ensures that it has a central role in cellular energy metabolism. The utility of this redox potential is, however, counterbalanced by the propensity of iron to generate free radicals and damage cell membranes through lipid peroxidation. Genomic investment and redundancy in mechanisms to control iron availability at the cellular level illustrates both its importance and potential for toxicity.

Iron homeostasis depends on the regulation of iron absorption from the intestine as there are no pathways for iron excretion. On average, 1-2 mg enters the adult human body on a daily basis and a variable amount leaves via sloughing of skin and mucosal cells. Diets rich in heme iron and vitamin C promote iron absorption. Meat and nonanimal foods such as legumes and green leafy vegetables combine readily available heme iron with promoters of absorption and utilization of non-heme iron. Phytate-containing foods, e.g., cereals, inhibit absorption. Non-heme iron is reduced and solubilized to the ferrous form in the proton rich environment of the proximal duodenum and actively transported across the enterocyte. The transport of ferrous iron through the enterocyte represents the primary site of iron homeostasis - it can be stored as ferritin, lost through sloughing of intestinal cells, or exported systemically.

Transferrin binds and solubilizes ferric iron exported from the enterocyte with high affinity and transports it to cells. Uptake and internalization of iron-transferrin by endocytosis is followed by its dissociation at lower intracellular pH and storage of iron in cytoplasmic ferritin molecules. Iron absorption, however, does not fulfil the majority of daily hemopoietic requirement. Senescent red blood cells are phagocytosed by reticuloendothelial macrophages, which recycle the iron from heme - they load the ferric iron back onto transferrin for reuse and this recycling of heme iron accounts for 80% of hemopoietic requirement.

Hemoglobin and intracellular ferritin, in the liver, bone marrow and spleen, account for over 99% of total body iron. Iron is more readily available than zinc and we have developed strategies to manage large fluxes of iron. Conditions characterized by hemolysis demonstrate the complex adaptive mechanisms that protect cells from episodes of flux.

Zinc is the twenty-fifth most abundant element comprising less than 0.01% of the earth's crust. Its single oxidant state enables it to hydolyze bonds involving carboxyl and amino groups and its ability to form stable complexes with sulfur and nitrogen atoms is utilized in stabilizing proteins. It has structural and regulatory roles in numerous enzymes, signaling pathways, and gene transcription systems essential for growth, reproduction, and metabolism. Up to 2 g of zinc is present in an adult man but most (95%) is locked away in pools from which it cannot rejoin the circulation and influence plasma levels, e.g., muscle and bone. Small plasma and liver pools are accessible and labile and act as the only reserve available in dietary deficiency. Zinc homeo-stasis is thus dependent on dietary intake and the average man has an intake of 10mgday_1. Meat is a good source of zinc but plant sources (e.g., lentils and cereals) are often compromised by the presence of phytate, which inhibits absorption.

Plasma zinc is 99% bound to albumin and other low molecular weight proteins. Plasma zinc makes up only a small percentage of body zinc. The control of zinc flux at the cellular level is much less well characterized than that of iron.

Metallothionens are a group of intracellular monomeric polypeptides that bind zinc and serve as homeostatic modulators of zinc availability. Relatively little is known of how zinc enters immune cells and how it influences function. Recently, a family of zinc transport genes (ZnT 1-4) has been cloned. ZnT 1 is associated with zinc efflux and expression of this gene is regulated by zinc intake. Further work is needed to clarify the role of this family in zinc transport and its possible regulatory influences, e.g., zinc status and inflammation. Zinc deficiency is difficult to identify both clinically and biochemically and only in the last decade has the widespread nature of this deficiency been recognized particularly in children in developing countries.

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