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DMT1 is not essential for Cu uptake from blood by internal organs

Divalent metal transporter 1 (DMT1) is the main mechanism by which Fe(II) is imported into enterocytes from the intestinal lumen. This uptake is inhibited by Cu(I) and some divalent metal ions; knockdown of expression is accompanied by a reduction in Cu as well as Fe uptake. In contrast, cells of internal organs mainly obtain their Fe from blood plasma transferrin by receptor mediated endocytosis, and DMT1 is mainly localized in endosomes, implying little would be at the cell surface to mediate Cu uptake. To verify this, we compared initial (1h) rates of uptake of tracer 64Cu(II) by organs of virgin and lactating Belgrade rats with those in the background (Fisher) strain. Lactation greatly increased 64Cu uptake by the mammary gland and reduced uptake by liver; but no significant differences ascribable to lack of DMT1 were detected in any of the organs tested. HepG2 cells were used to further explore potential involvement of DMT1 by measuring initial (30 min) rates of 64Cu uptake from purified plasma proteins. No inhibition by Fe(II) was observed. Conversely, uptake of 59Fe(II) (± ascorbate) was not inhibited by excess Cu(I) or Cu(II). Pretreatment of cells with Fe for 24h enhanced rates of 59Fe(II) uptake but did not alter those for Cu. Fe pretreatment did not alter DMT1 mRNA or protein expression. We conclude that DMT1 is unlikely to be important for uptake of Cu by cells of internal organs. Supported in part by USPHS Grant HD 46949.