Intestinal DMT1 Is Essential for Optimal Assimilation of Dietary Copper in Male and Female Mice with Iron-Deficiency Anemia

Wang, Xiaoyu; Flores, Shireen; Ha, Jung‐Heun; Doguer, Caglar; Woloshun, Regina R.; Xiang, Ping; Grosche, Astrid; Vidyasagar, Sadasivan; Collins, James F.

doi:10.1093/jn/nxy111

Cited by 21 publications

(16 citation statements)

References 51 publications

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“…Fe 2+ absorption is based on the principle of active transport with a divalent metal transporter (DMT-1) in the apical membrane of the duodenum and the upper part of the small intestine [53,54]. The divalent metal transporter 1 (DMT1) is a non-selective transporter of bivalent metal ions, including iron, zinc, copper, manganese, cobalt, and cadmium, whose transport through the membrane occurs via proton-coupled divalent metal ion transporters [55,56]. Fe levels may also be influenced by the expression of intestinal copper transporting P-type ATPases copper-transporting ATPase α (ATP7A), which indirecly impairs Fe absorption by affecting the expression of Fe transporters [57].…”

Section: Iron (Fe)mentioning

confidence: 99%

The Role of Fe, Zn, and Cu in Pregnancy

2020

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Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein synthesis. Fe, Cu, and Zn have a significant impact on the health of pregnant women and in the development of the fetus, as well as on the health of the newborn. A proper concentration of these elements in the body of women during pregnancy reduces the risk of complications such as anemia, induced hypertension, low birth weight, preeclampsia, and postnatal complications. The interactions between Fe, Cu, and Zn influence their availability due to their similar physicochemical properties. This most often occurs during intestinal absorption, where metal ions compete for binding sites with transport compounds. Additionally, the relationships between these ions have a great influence on the course of reactions in the tissues, as well as on their excretion, which can be stimulated or delayed. This review aims to summarize reports on the influence of Fe, Cu, and Zn on the course of single and multiple pregnancies, and to discuss the interdependencies and mechanisms occurring between Fe, Cu, and Zn.

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Section: Iron (Fe)mentioning

confidence: 99%

The Role of Fe, Zn, and Cu in Pregnancy

2020

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“…Copper transporter 1 (Ctr1) is the main intestinal copper transporter (at least in mice) [ 44 ], while the main iron transporter (in rodents and probably humans) is divalent metal-ion transporter 1 (Dmt1) [ 45 ]. Interestingly, Dmt1 has been suggested to also transport copper [ 46 , 47 , 48 ], but to our knowledge, there is no evidence that Ctr1 can transport or otherwise interact with enteral iron. Logically, excess enteral iron could block copper transport by Ctr1, possibly by competing for copper binding to the pore region of the Ctr1 heterotrimer.…”

Section: Discussionmentioning

confidence: 99%

Dietary Iron Intake in Excess of Requirements Impairs Intestinal Copper Absorption in Sprague Dawley Rat Dams, Causing Copper Deficiency in Suckling Pups

Lee

Collins

2021

Biomedicines

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Physiologically relevant iron-copper interactions have been frequently documented. For example, excess enteral iron inhibits copper absorption in laboratory rodents and humans. Whether this also occurs during pregnancy and lactation, when iron supplementation is frequently recommended, is, however, unknown. Here, the hypothesis that high dietary iron will perturb copper homeostasis in pregnant and lactating dams and their pups was tested. We utilized a rat model of iron-deficiency/iron supplementation during pregnancy and lactation to assess this possibility. Rat dams were fed low-iron diets early in pregnancy, and then switched to one of 5 diets with normal (1×) to high iron (20×) until pups were 14 days old. Subsequently, copper and iron homeostasis, and intestinal copper absorption (by oral, intragastric gavage with 64Cu), were assessed. Copper depletion/deficiency occurred in the dams and pups as dietary iron increased, as evidenced by decrements in plasma ceruloplasmin (Cp) and superoxide dismutase 1 (SOD1) activity, depletion of hepatic copper, and liver iron loading. Intestinal copper transport and tissue 64Cu accumulation were lower in dams consuming excess iron, and tissue 64Cu was also low in suckling pups. In some cases, physiological disturbances were noted when dietary iron was only ~3-fold in excess, while for others, effects were observed when dietary iron was 10–20-fold in excess. Excess enteral iron thus antagonizes the absorption of dietary copper, causing copper depletion in dams and their suckling pups. Low milk copper is a likely explanation for copper depletion in the pups, but experimental proof of this awaits future experimentation.

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“…Copper, another essential element, is released from the diet in acid stomach content and uptaken in the form of copper(II) by DMT1 and human copper transporter 1 (hCTR1) [81,82]. It is noteworthy that copper is secreted into the gastrointestinal tract, and further reuptake represents even more copper than what is present in food [83].…”

Section: Copper Metabolism Diseases Connected With Its Overload and Current Treatmentmentioning

confidence: 99%

Chelators for Treatment of Iron and Copper Overload: Shift from Low-Molecular-Weight Compounds to Polymers

et al. 2021

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Iron and copper are essential micronutrients needed for the proper function of every cell. However, in excessive amounts, these elements are toxic, as they may cause oxidative stress, resulting in damage to the liver and other organs. This may happen due to poisoning, as a side effect of thalassemia infusion therapy or due to hereditary diseases hemochromatosis or Wilson’s disease. The current golden standard of therapy of iron and copper overload is the use of low-molecular-weight chelators of these elements. However, these agents suffer from severe side effects, are often expensive and possess unfavorable pharmacokinetics, thus limiting the usability of such therapy. The emerging concepts are polymer-supported iron- and copper-chelating therapeutics, either for parenteral or oral use, which shows vivid potential to keep the therapeutic efficacy of low-molecular-weight agents, while avoiding their drawbacks, especially their side effects. Critical evaluation of this new perspective polymer approach is the purpose of this review article.

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Intestinal DMT1 Is Essential for Optimal Assimilation of Dietary Copper in Male and Female Mice with Iron-Deficiency Anemia

Cited by 21 publications

References 51 publications

The Role of Fe, Zn, and Cu in Pregnancy

The Role of Fe, Zn, and Cu in Pregnancy

Dietary Iron Intake in Excess of Requirements Impairs Intestinal Copper Absorption in Sprague Dawley Rat Dams, Causing Copper Deficiency in Suckling Pups

Chelators for Treatment of Iron and Copper Overload: Shift from Low-Molecular-Weight Compounds to Polymers

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