ReviewIron metabolism and toxicity
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).
References (97)
- et al.
A novel mammalian iron-regulated protein involved in intracellular iron metabolism
J. Biol. Chem.
(2000) - et al.
Decreased liver hepcidin expression in the hfe knockout mouse
Blood Cells, Mol. Dis.
(2002) - et al.
Chemistry and biology of eukaryotic iron metabolism
Int. J. Biochem. Cell Biol.
(2001) - et al.
Penetrance of 845G–A (C282Y) HFE hereditary haemochromatosis mutation in the USA
Lancet
(2002) - et al.
Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis
Lancet
(2003) - et al.
Juvenile hemochromatosis
Semin. Hematol.
(2002) - et al.
Structure of the human transferrin receptor–transferrin complex
Cell
(2004) - et al.
C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation
Cell
(2001) - et al.
H-Ferritin subunit overexpression in erythroid cells reduces the oxidative stress response and induces multidrug resistance properties
Blood
(1999) Regulators of iron balance in humans
Blood
(1994)
Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation
Blood
Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to serum transferrin saturation and non-transferrin-bound iron
Blood
The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition
Mol. Cell
The role of free radicals and catalytic metal ions in human disease: an overview
Methods Enzymol.
Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing
Blood
Oxygen and iron regulation of iron regulatory protein 2
J. Biol. Chem.
The ferritins: molecular properties, iron storage function and cellular regulation
Biochim. Biophys. Acta
Balancing acts; molecular control of mammalian iron metabolism
Cell
Iron overload and its association with cancer risk in humans: evidence for iron as a carcinogenic metal
Mutat. Res.
HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype
Blood
Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system
J. Biol. Chem.
The labile iron pool: characterization, measurement, and participation in cellular processes
Free Radical Biol. Med.
Repression of ferritin expression increases the labile iron pool, oxidative stress, and short-term growth of human erythroleukemia cells
Blood
Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family
J. Biol. Chem.
LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity
FEBS Lett.
A novel duodenal iron-regulated transporter IREG1, implicated in the basolateral transfer of iron to the circulation
Mol. Cell
Myeloperoxidase derived hypochlorous acid antagonizes the oxidative stress mediated activation of iron regulatory protein 1
J. Biol. Chem.
Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice
Blood
The copper–iron connection: hereditary aceruloplasminemia
Semin. Hematol.
Genetic heterogeneity underlies juvenile hemochromatosis phenotype: analysis of three families of northern Greek origin
Blood Cells, Mol. Dis.
Hepcidin, a urinary antimicrobial peptide synthesized in the liver
J. Biol. Chem.
Juvenile hemochromatosis locus maps to chromosome 1q
Am. J. Hum. Genet.
Iron homeostasis: new tales from the crypt
Blood
The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties
Free Radical Biol. Med.
Iron-induced carcinogenesis: the role of redox regulation
Free Radical Biol. Med.
Pathogenesis and treatment of anaemia of chronic disease
Blood Rev.
An iron delivery pathway mediated by a lipocalin
Mol. Cell
Decreased hepcidin mRNA expression in thalassemic mice
Br. J. Haematol.
Disorders of iron metabolism
N. Engl. J. Med.
Iron homeostasis: insights from genetics and animal models
Nat. Rev., Genet.
Iron–sulfur clusters: nature's modular, multipurpose structures
Science
ROS, stress-activated kinases and stress signaling in cancer
EMBO Rep.
Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor
Genes Dev.
A conserved family of prolyl-4-hydroxylases that modify HIF
Science
The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22
Nat. Genet.
Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity
Am. J. Hematol.
Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease
Nat. Genet.
Iron and hepatocellular carcinoma
J. Gastroenterol. Hepatol.
Cited by (758)
Preferences of interaction sites for proton-induced photophysical signalling with a derivatized rhodamine probe
2024, Journal of Molecular StructureRecent advances in Fe-based bioresorbable stents: Materials design and biosafety
2024, Bioactive MaterialsFluorescent probe based on acyclic cucurbituril to detect Fe<sup>3+</sup> ions in living cells
2023, Journal of Molecular Liquids