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LIVER AND BILIARY TRACT

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

¹Microminerals Laboratory and ²Bioinformatic and Gene Expression Laboratory, Institute of Nutrition and Food Technology and ³Faculty of Science, Department of Biology, University of Chile, Casillo 138-11 Santiago, Chile

Submitted 16 July 2003 ; accepted in final form 20 February 2004

Divalent metal transporter #1 (DMT1) is responsible for intestinal nonheme Fe apical uptake. However, DMT1 appears to have an additional function in Cu transport in intestinal cells. Because the liver has an essential role in body Cu homeostasis, we examined the potential involvement of Cu in the regulation of DMT1 expression and activity in Hep-G2 cells. Cells exposed to 10 µM Cu exhibited a 22-fold increase in Cu content and a twofold decrease in Fe content compared with cells maintained in 0.4 µM Cu. ⁶⁴Cu uptake in Cu-deficient Hep-G2 cells showed a twofold decrease in K_m compared with cells grown in 10 µM Cu. The decreased K_m may represent an adaptive response to Cu deficiency. Cells treated with >50 µM Cu, showed an eightfold increase in cytosolic metallothionein. DMT1 protein decreased (35%), suggesting that intracellular Cu caused a reduction of DMT1 protein levels. Our data indicate that, as a result of Cu overload, Hep-G2 cells reduced their Fe content and their DMT1 protein levels. These findings strongly suggest a relationship between Cu and Fe homeostasis in Hep-G2 cells in which Cu accumulation downregulates DMT1 activity.

uptake; iron; copper; divalent metal transporter #1; metallothionein

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