Copper as a cofactor in iron transport —
the complete data set

The ferroxidase hypothesis and its experimental confirmation

In the 1960s researchers found that copper deficiency in laboratory animals leads to an anaemia resembling that of iron deficiency — even though the iron stores were full. The hypothesis: without copper, iron cannot be converted into its transportable form.

Historical context: Osaki, Johnson and the copper protein in serum

The work of Osaki and Johnson (1966) showed that ceruloplasmin — a copper-containing glycoprotein with six bound copper atoms — catalyses the oxidation of Fe²⁺ to Fe³⁺. Only in the trivalent form can iron bind to the transport protein transferrin and be distributed through the bloodstream.

The ferroxidase activity of ceruloplasmin has since been reproduced in numerous studies and forms the biochemical basis for the EU-authorised claim on the copper-iron relationship.

Ceruloplasmin is synthesised in the liver. The six copper atoms are loaded into the apoprotein by the ATPase ATP7B. Where this transporter is genetically defective (Wilson disease), ceruloplasmin loading is disturbed — a clinically relevant indication of how iron distribution depends on copper availability.

Copper in intestinal iron absorption

Absorption of iron from food takes place mainly in the duodenum and upper jejunum. Non-heme iron, which occurs in plant foods, is first reduced from Fe³⁺ to Fe²⁺ by the ferric reductase DcytB at the apical membrane of the enterocyte. Import then follows via the transporter DMT1.

Hephaestin and the basolateral membrane of the enterocyte

For export from the enterocyte into the blood plasma, the membrane protein ferroportin is available on the basolateral side. Iron exits in the divalent form — but transferrin in the blood binds only trivalent iron. This is where hephaestin comes in: this membrane-bound copper enzyme oxidises Fe²⁺ to Fe³⁺ immediately after export.

Hephaestin is structurally closely related to ceruloplasmin, but while ceruloplasmin circulates freely in the plasma, hephaestin remains anchored in the cell membrane. Both proteins contain copper as a cofactor and perform a comparable ferroxidase function — each in a different place.

Animal data show that copper deficiency reduces hephaestin activity and thereby slows the passage of iron into the blood. The iron remains in the enterocyte and is excreted after a few days when the cell is naturally shed.

Reference value and food sources of copper

The daily reference value for copper under EU Regulation 1169/2011 is 1 mg. The following foods are among the best-known natural sources of copper:

Bioavailability and interactions with zinc

Copper absorption takes place predominantly in the stomach and upper small intestine. Uptake occurs via the transporter CTR1, with copper being absorbed in the monovalent form (Cu⁺). Divalent copper compounds from food are enzymatically reduced beforehand.

High zinc doses can impair copper absorption, because both metals compete for binding sites on the protein metallothionein. At customary dietary amounts this interaction is generally of little practical significance. Even so, when zinc and copper preparations are taken together, an interval between them is advisable.

Clinical observations in copper deficiency

Pronounced copper deficiency is rare in industrialised countries, but it does occur in certain clinical situations: with long-term tube feeding without added copper, after bariatric surgery, or with chronic zinc excess from high-dose supplements.

Findings resembling iron deficiency despite full iron stores

The characteristic haematological picture of copper deficiency includes a microcytic or normocytic anaemia that is clinically hard to distinguish from classic iron deficiency. The decisive difference: ferritin values (a measure of iron stores) are normal or even elevated, while serum iron and transferrin saturation are reduced.

This pattern is explained by the fact that iron is indeed present in the tissue but cannot be converted into its transportable form without functioning ceruloplasmin. It is a distribution problem, not a shortage of iron itself.

In documented cases, normalising copper intake leads to a restoration of ceruloplasmin activity and to an increase in transferrin saturation — indirect evidence for the role of copper in iron transport.

For reference: four questions on the copper-iron relationship

Why is copper mentioned in connection with iron metabolism?

Copper is a cofactor of two ferroxidases — ceruloplasmin in blood plasma and hephaestin at the intestinal wall. Both enzymes oxidise divalent iron to trivalent iron, which can then bind to transferrin and be transported. Without this copper-dependent oxidation, orderly iron transport in the body would be impaired.

Which foods supply appreciable amounts of copper?

Beef liver, oysters, sesame seeds and cashew nuts are among the foods richest in copper. Dark chocolate, sunflower seeds and pulses also contribute to supply. The EU reference value is 1 mg per day.

What does the authorised claim on iron transport mean?

The claim “Copper contributes to normal iron transport in the body” is authorised under Regulation (EU) No 432/2012. It is based on a scientific opinion from EFSA and may be used for foods that contain at least 15 % of the reference value per portion. The claim describes a physiological function, not a therapeutic effect.

Are there interactions between copper and other minerals?

High zinc doses can impair copper absorption in the intestine, because both metals partly compete for the same binding sites. When taking dietary supplements, an interval between zinc and copper preparations is advisable. The stated recommended daily intake should not be exceeded.