Copper overload affects copper and iron metabolism in Hep-G2 cells

Arredondo, Miguel; Cambiazo, Verónica; Tapia, Lucı́a; González-Agüero, Mauricio; Núñez, Marco T.; Uauy, Ricardo; González, Maurício

doi:10.1152/ajpgi.00297.2003

Cited by 38 publications

(20 citation statements)

References 56 publications

(67 reference statements)

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“…We showed that the incubation of Caco-2 cells with Fe, Cu or Zn, affects Fe metabolism. Similar results in Caco-2 and HepG2 cells were reported earlier by us (Arredondo et al, 2000;2004). As expected, when extracellular iron concentrations increased in the media, intracellular Fe increased as well.…”

Section: Effect Of Different Molar Ratios Over 55 Fe or 64 Cu Uptakesupporting

confidence: 91%

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Inhibition of iron and copper uptake by iron, copper and zinc

Arredondo¹,

Martínez²,

Núñez

et al. 2006

Biol. Res.

118

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Interactions of micronutrients can affect absorption and bioavailability of other nutrients by a number of mechanisms. In aqueous solutions, and at higher uptake levels, competition between elements with similar chemical characteristics and uptake process can take place. The consequences of these interactions may depend on the relative concentrations of the nutrients. In this work, we measure the effects of increasing concentrations of iron, zinc, and copper on iron and copper uptake in Caco-2 cells. Intracellular Fe or Cu levels were affected by incubating with increased concentrations of metals. However, when the cells already had different intracellular metal concentration, the uptake of Fe or Cu was nor affected. In competition studies, we showed that Cu and Zn inhibited Fe uptake, and while Fe inhibited Cu uptake, Zn did not. When the three metals were given together (1: 1: 1 ratio), Fe or Cu uptake was inhibited ~40%. These results point to a potential risk in the absorption and bioavailability of these minerals by the presence of other minerals in the diet. This aspect must be considered in food supplementation and fortification programs.

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Section: Effect Of Different Molar Ratios Over 55 Fe or 64 Cu Uptakesupporting

confidence: 91%

“…Caco-2 cells were grown in Iscove´s medium + 10% FBS and cultured as described elsewhere (Arredondo et al, 2004). Approximately 1x10 5 cells were grown in bottles (25 cm 2 growth area) for seven days at 37º C, 5% CO 2 .…”

Section: Cell Growthmentioning

confidence: 99%

Inhibition of iron and copper uptake by iron, copper and zinc

Arredondo¹,

Martínez²,

Núñez

et al. 2006

Biol. Res.

118

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“…This seems to correspond with recent findings. Exposing Hep-G2 cells -a model of hepatic cells -to increasing extracellular Cu concentrations resulted in a decrease of Fe and Zn concentration intracellular, measuring Fe and Zn contents by total-reflection X-ray fluorescence spectrometry [38]. These data indicate that Cu overload at least in Hep-G2 cell lines reduces their Fe and Zn content presumably by downregulating DMT1 activity.…”

Section: Elemental Dependenciesmentioning

confidence: 88%

“…MT is a cysteine-based protein that transports metals such as Cu and Zn. The recently described divalent metal transporter (DMT1) binds not only Fe but also Cu [36][37][38]. These biochemical dependencies should be elucidated by inspecting and analysing regions with different Fe concentrations in the scans of HC.…”

Section: Elemental Dependenciesmentioning

confidence: 99%

Iron, copper, zinc and bromine mapping in cirrhotic liver slices from patients with hemochromatosis studied by microscopic synchrotron radiation X-ray fluorescence analysis in continuous scanning mode

Osterode¹,

Falkenberg²,

Höftberger³

et al. 2007

Spectrochimica Acta Part B: Atomic Spectroscopy

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Iron (Fe) and copper (Cu) are essential metals in physiological cell metabolism. While Fe is easy to determine biochemically in histological slices, Cu and zinc (Zn) distribution is frequently critical in confirming the presence of an overload in disturbed Fe/Cu metabolism. To analyze Fe, Cu and Zn in a near histological resolution, energy dispersive microscopic synchrotron radiation X-ray fluorescence was applied.In normal liver tissue, after fixation and imbedding in paraffin, mean Fe, Cu and Zn concentrations were 152 ± 54, 20.1 ± 4.3 and 88.919.5 μg/g sample weight, respectively. No substantial, characteristic differences in their distribution were found in the two-dimensional scans. In slices from patients with hemochromatosis mean Fe, Cu and Zn concentrations were 1102 ± 539, 35.9 ± 14.6 and 27.2 ± 6.7 μg/g sample weight, respectively. Additionally, a significant decrease in phosphorus and sulphur concentrations existed. An increased Cu around cirrhotic regenerations nodules is mostly associated with a lymphocytic infiltration in this region. Analyzing concentrations of Fe in different regions of the samples show a clear negative dependency between Fe and Cu, Cu and Zn, but a positive one between Fe and Zn.Conclusion: With a focal beam size of 15 μm in diameter a resolution of the elemental distribution was achieved which is widely comparable with stained histological slices (20× light microscope). The analysis of simultaneous determined elements reveals metabolic differences between Fe, Cu and Zn in liver tissue from patients with hemochromatosis.

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“…In the present work we have shown that in HEK 293 cells, a human cell line, hCTR1, is responsible for at least 80% of the Cu uptake. It is interesting that in intestinal cells it has been reported that Cu uptake is stimulated (and not decreased) by exposure to elevated Cu levels (22,23). It has yet to be shown which of the Cu uptake proteins mediates the uptake pathway in these intestinal cells.…”

Section: Discussionmentioning

confidence: 99%

Stable Plasma Membrane Levels of hCTR1 Mediate Cellular Copper Uptake

Eisses

Chi

Kaplan

2005

Journal of Biological Chemistry

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The human copper transporter 1 (hCtr1), when heterologously overexpressed in insect cells, mediates saturable Cu uptake. In mammalian expression systems, a rapid Cu-dependent internalization of hCtr1 has been reported in cells that overexpress epitope-tagged hCtr1 when exposed to Cu in the external medium. This finding led to the suggestion that such internalization may be a step in the hCtr1 transmembrane Cu transport mechanism. We have demonstrated that preincubation in Cu-containing media of sf9 cells stably expressing hCtr1 has no effect on the initial rate of Cu transport. Furthermore, Western blot analyses of fractionated sf9 cell membranes show no evidence of a regulatory Cu-dependent internalization from the plasma membrane. In similar studies on human embryonic kidney (HEK) 293 cells, we showed that incubation with Cu does not alter the initial rate of Cu uptake mediated by endogenous levels of hCtr1 compared with untreated cells. Confirmation that hCtr1 mediates this transport is provided by specific small interfering RNA-dependent decreases in hCtr1 protein levels and in Cu transport rates. Western blot analysis and confocal microscopy of human embryonic kidney 293 cells showed that the majority of hCtr1 protein is localized at the plasma membrane and no significant internalization is detected upon Cu treatment. We concluded that internalization of hCtr1 is not a required step in the transport pathway; we suggest that oligomeric hCtr1 acts as a conventional transporter providing a permeation pathway for Cu through the membrane and that internalization of endogenous hCtr1 in response to elevated extracellular Cu levels does not play a significant regulatory role in Cu homeostasis.

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Copper overload affects copper and iron metabolism in Hep-G2 cells

Cited by 38 publications

References 56 publications

Inhibition of iron and copper uptake by iron, copper and zinc

Inhibition of iron and copper uptake by iron, copper and zinc

Iron, copper, zinc and bromine mapping in cirrhotic liver slices from patients with hemochromatosis studied by microscopic synchrotron radiation X-ray fluorescence analysis in continuous scanning mode

Stable Plasma Membrane Levels of hCTR1 Mediate Cellular Copper Uptake

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