Review
Iron metabolism and toxicity

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Abstract

Iron is an essential nutrient with limited bioavailability. When present in excess, iron poses a threat to cells and tissues, and therefore iron homeostasis has to be tightly controlled. Iron's toxicity is largely based on its ability to catalyze the generation of radicals, which attack and damage cellular macromolecules and promote cell death and tissue injury. This is lucidly illustrated in diseases of iron overload, such as hereditary hemochromatosis or transfusional siderosis, where excessive iron accumulation results in tissue damage and organ failure. Pathological iron accumulation in the liver has also been linked to the development of hepatocellular cancer. Here we provide a background on the biology and toxicity of iron and the basic concepts of iron homeostasis at the cellular and systemic level. In addition, we provide an overview of the various disorders of iron overload, which are directly linked to iron's toxicity. Finally, we discuss the potential role of iron in malignant transformation and cancer.

Section snippets

Chemical properties and biological functions of iron

Iron is a component of several metaloproteins and plays a crucial role in vital biochemical activities, such as oxygen sensing and transport, electron transfer, and catalysis (Aisen et al., 2001). Iron is thus indispensable for life. The biological functions of iron are based on its chemical properties, e.g., its capacity to form a variety of coordination complexes with organic ligands in a dynamic and flexible mode, and its favorable redox potential to switch between the ferrous, Fe(II), and

Toxicity of iron

The efficiency of Fe(II) as an electron donor and of Fe(III) as an electron acceptor, with a redox potential compatible with the constrains of the cellular environment, is a fundamental feature for many biochemical reactions and renders iron to an essential mineral and nutrient. However, this very property turns iron into a potential biohazard, because under aerobic conditions, iron can readily catalyze the generation of noxious radicals. Iron's toxicity is largely based on Fenton and

Cellular iron metabolism

Iron-loaded transferrin binds to its specific receptor on the cell surface, the transferrin receptor 1 (TfR1) (Ponka et al., 1998). The complex undergoes endocytosis (Cheng et al., 2004) and iron is released from transferrin, following acidification of the endosome to pH ∼5.5, and transported across the endosomal membrane by the divalent metal transporter DMT1. Internalized iron is utilized for metabolic purposes (incorporation into iron-containing proteins) and excess is detoxified by

Iron distribution in humans

The human body contains approximately 3–5 g of iron (45–55 mg/kg of body weight in adult women and men, respectively), distributed as illustrated in Fig. 3. The majority of body iron (∼60–70%) is utilized within hemoglobin in circulating red blood cells (Andrews, 1999, Ponka, 1997). Other iron-rich organs are the liver and muscles. Approximately 20–30% of body iron is stored in hepatocytes and in reticuloendothelial macrophages, to a large extent within ferritin and its degradation product

Hereditary hemochromatosis

Hereditary hemochromatosis (HH) is an autosomal recessive disorder in which inappropriately high absorption of dietary iron eventually leads to iron accumulation in tissue parenchymal cells and severe organ damage (Fleming and Sly, 2002, Pietrangelo, 2004a). Notably, macrophages are spared from iron loading, at least during the early stages of the disease. Excessive iron accumulation is observed after the age of 40 predominantly in the liver, but also in pancreas, pituitary, heart, joints, and

Iron toxicity and cancer

In contrast to other metals, such as arsenic, chromium, or nickel, iron does not have carcinogenic properties per se; nevertheless, iron overload is clearly associated with a high risk for carcinogenesis (Huang, 2003). This is illustrated by the fact that a common complication of HH is the development of hepatocellular carcinoma (Deugnier and Turlin, 2001), affecting approximately 30% of patients with pathological iron deposition in parenchymal tissue. Other forms of cancer, including

Acknowledgments

KP is a scholar of the Canadian Institutes of Health Research (CIHR) and a researcher of the Canada Foundation for Innovation (CFI).

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