Cellular Components of Blood
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2020
Almost all iron (in the ferrous [Fe2+] state) absorption occurs in the duodenum. Factors favouring the absorption of iron include gastric acid and reducing agents, which maintain the soluble iron in the ferrous state. Iron absorption is reduced by alkali and chelating agents such as phytates and phosphates, which form insoluble iron complexes. Fe2+ iron is transported into the enterocyte via divalent metal transporter 1 (DMT1) across the brush border of duodenal enterocytes. Within these cells, some Fe2+ binds to apoferritin and is stored as ferritin in the ferric [Fe3+] state and is shed into the gut lumen at the end of the lifespan of the these cells (3–4 days). The remaining Fe2+ ions are transported out of the enterocytes by ferroportin 1 in the basolateral cells of the duodenal enterocyte. In the plasma, Fe2+ is converted to Fe3+ and bound to transferrin, a plasma glycoprotein. Normally, it is about 35% saturated with iron. Normal plasma iron level is 19–23 μmol/L.
The Contribution of Iron and Transition Metal Micronutrients to Diabetes and Metabolic Disease
Emmanuel C. Opara, Sam Dagogo-Jack in Nutrition and Diabetes, 2019
Systemic and cellular iron metabolism have been the subject of excellent recent reviews [9–11] and will be only briefly recapitulated here (Figure 15.1). Intestinal free ferric (Fe3+) iron is reduced to ferrous Fe2+ by duodenal cytochrome B (DCTB) and enters duodenal enterocytes by way of the divalent metal-ion transporter 1 (DMT1) and possibly other carriers. Dietary heme is directly absorbed into enterocytes, where iron is released by heme oxygenase (HMOX). Ferrous iron exits the enterocytes through the iron export channel ferroportin (FPN). After oxidization by hephaestin (HEPH), Fe3+ binds to transferrin (Tf) in the blood, which in turn binds to transferrin receptors (TfR) on the surface of target cells. In most cells (Figure 15.1, lower right), after endocytosis of TfR1 and acidification of the endosome, iron is released, reduced by STEAP (6-transmembrane epithelial antigen of the prostate), and enters the cytosol through DMT1, where it is used (e.g., for heme or Fe-S-cluster synthesis in mitochondria) or, if in excess, sequestered by ferritin. Apoferritin secreted into the circulation is a marker for tissue iron stores, although the trigger for its secretion versus use to sequester more iron is not known. The intracellular trafficking of iron is much more complicated than indicated in the figure. For example, iron is highly controlled and chaperoned to its various targets, as ferrous iron or after iron-sulfur cluster synthesis, by mechanisms that are still under study [6].
Iron
Judy A. Driskell, Ira Wolinsky in Sports Nutrition, 2005
Absorption of iron occurs in the upper part of the small intestine. Two forms of iron are found in foods, heme iron and non-heme iron. Heme iron is found in meat, fish and poultry and nonheme iron is found in plants and dairy products. More than 80% of the dietary iron in the American diet is nonheme iron. Before absorption can occur, nonheme iron must be converted from the ferric to the ferrous state. Nonheme iron appears to be transported across the duodenal cell membrane by a divalent metal transporter protein (DMT1). Synthesis of DMT1 is inversely proportional to the mucosal cell iron content.1
Chronic cadmium exposure in Japanese quails perturbs serum biochemical parameters and enzyme activity
Published in Drug and Chemical Toxicology, 2020
Damir Suljević, Erna Islamagić, Anida Čorbić, Muhamed Fočak, Filip Filipić
Cadmium is a toxic heavy metal classified as a human carcinogen. Correlation between cadmium exposure and lung and prostate cancer in humans was found when inhaled cadmium in rodents caused pulmonary adenocarcinoma (Waalkes 2000). Besides the gastrointestinal system, the respiratory system is another pathway for cadmium entry into the body. About 50% of cadmium is absorbed from tobacco (Zalups and Ahmad 2003). Cadmium binds to the sulfhydryl cysteine radical in keratinocytes, then penetrates the blood by binding to metallothionein (Fasanya-Odewumi et al. 1998). Divalent metal transporter 1 (DMT1) and albumins have a high affinity for cadmium and distribute cadmium to different organs (Himeno et al. 2002). The biological half-life of cadmium is estimated at 15 to 20years (Kayankarnna et al. 2013). Cadmium also accumulates in the liver and kidneys due to the high content of metallothionein (Joseph 2009). Järup and Alfvén (2004) reported the connection between cadmium and diseases such as bone metabolism impairment and fragility, emphysema, immune system suppression and diabetes (Valko et al. 2005). Long-term exposure to cadmium in the Japanese population has led to the development of itai-itai disease. Characteristics of the disease include osteomalacia, osteoporosis, skeletal deformities, followed by changes in glucose, calcium, and amino acid levels (Inaba et al.2005).
Protective association of A-T-T haplotype of DMT1 gene against risk of human age-related nuclear cataract
Published in Ophthalmic Genetics, 2019
Rajkumar Sankaranarayanan, Nair Gopinathan Vidya, Abhay Raghukant Vasavada
Divalent metal transporter 1 (DMT1), an isoform of natural resistance-associated macrophage protein 2 (NRAMP2), mediates transport of ferrous iron from the lumen of the intestine into the enterocyte and export of iron from endocytic vesicles. It has an affinity not only for iron but also for other divalent cations including cadmium, cobalt, copper, lead, manganese, nickel, and zinc. DMT1 gene is located on chromosome 12q13 in humans and expresses four major isoforms; two with iron-responsive elements (1A/+IRE and 2/+IRE) and two without iron-responsive elements (1A/-IRE, and 2/-IRE) (34). Mutations or polymorphisms of DMT1 gene may have an impact on human health by disturbing metal trafficking (34,35) and augmenting systemic and tissue overload of divalent metal ions (36). Association of different genetic polymorphisms of DMT1 with age-related macular degeneration (37), Alzheimer’s disease (38), hereditary hemochromatosis (39), microcytic anemia (40,41), Parkinson’s disease (42), and Wilson’s disease (43) have been reported.
SARS-CoV-2 Infection Dysregulates Host Iron (Fe)-Redox Homeostasis (Fe-R-H): Role of Fe-Redox Regulators, Ferroptosis Inhibitors, Anticoagulants, and Iron-Chelators in COVID-19 Control
Published in Journal of Dietary Supplements, 2023
Sreus A.G. Naidu, Roger A. Clemens, A. Satyanarayan Naidu
Fe-R-H depends on the expression and activity of iron-carriers, iron-transporters, iron-regulators, and iron-storage proteins. Divalent metal transporter 1 (DMT1) located in the intestinal enterocyte sequesters non-heme iron from the diet, and ferroportin 1 (FPN1) exports iron into the circulation (28). Plasma TF and LF transport iron to various tissues and cells. After binding to transferrin receptor 1 (TfR1), the complex is endocytosed and release iron into the cytoplasm (29). Free iron is utilized either for metabolism, or sequestered by the cytosolic ferritin, as cellular iron reserve. Excess iron is exported from the cell via FPN1 and hepcidin (30). Intra-cellular IRPs modulate the expression of DMT1, TfR1, ferritin, and FPN1 via binding to the iron-responsive element (IRE) (31,32). The systemic Fe-R-H is mainly orchestrated by the hepcidin/FPN1 axis.