ABSTRACT Iron is an essential transition metal for mammalian cellular and tissue viability. It is critical to supplying oxygen through heme, the mitochondrial respiratory chain, and enzymes such as ribonucleotide reductase. Mammalian organisms have evolved with the means of regulating the metabolism of iron, because if left unregulated, the resulting excess amounts of iron may induce chronic toxicities affecting multiple organ systems. Several homeostatic mechanisms exist to control the amount of intestinal dietary iron uptake, cellular iron uptake, distribution, and export. Within these processes, numerous molecular participants have been identified because of advancements in basic cell biology and efforts in disease-based research of iron storage abnormalities. For example, dietary iron uptake across the intestinal duodenal mucosa is mediated by an intramembrane divalent metal transporter 1 (DMT1), and cellular iron efflux involves ferroportin, the only known iron exporter. In addition to duodenal enterocytes, ferroportin is present in other cell types, and exports iron into plasma. Ferroportin was recently discovered to be regulated by the expression of the circulating hormone hepcidin, a small peptide synthesized in hepatocytes. These recent studies on the role of hepcidin in the regulation of dietary, cellular, and extracellular iron have led to a better understanding of the pathways by which iron balance in humans is influenced, especially its involvement in human genetic diseases of iron overload. Other important molecular pathways include iron binding to transferrin in the bloodstream for cellular delivery through the plasma membrane transferrin receptor (TfR1). In the cytosol, iron regulatory proteins 1 and 2 (IRP1 and IRP2) play a prominent role in sensing the presence of iron in order to posttranscriptionally regulate the expression of TfR1 and ferritin, two important participants in iron metabolism. From a toxicological standpoint, posttranscriptional regulation of these genes aids in the sequestration, control, and hence prevention of cytotoxic effects from free-floating nontransferrin-bound iron. Given the importance of dietary iron in normal physiology, its potential to induce chronic toxicity, and recent discoveries in the regulation of human iron metabolism by hepcidin, this review will address the regulatory mechanisms of normal iron metabolism in mammals with emphasis on dietary exposure. It is the goal of this review that this information may provide in a concise format our current understanding of major pathways and mechanisms involved in mammalian iron metabolism, which is a basis for control of iron toxicity. Such a discussion is intended to facilitate the identification of deficiencies so that future metabolic or toxicological studies may be appropriately focused. A better knowledge of iron metabolism from normal to pathophysiological conditions will ultimately broaden the spectrum of the usefulness of this information in biomedical and toxicological sciences for improving and protecting human health.
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