Hepatic Copper Metabolism And The Role Of Atp7b

Copper is an essential nutrient needed for such diverse processes as mitochondrial respiration (cytochrome C), melanin biosynthesis (tyrosinase), dopamine metabolism (DOPA-mono-oxygenase), iron homeostasis (ceruloplasmin), antioxidant defense (superoxide dismutase), connective tissue formation (lysyl oxidase) and peptide amidation.

Dietary copper intake is approximately 1-2 mg/day. Quoted copper contents of foods are unreliable. While some foods, such as meats and shellfish, have consistently high copper con-centrations, others such as dairy produce are consistently low in copper. However, the copper content of cereals and fruits varies greatly with soil copper content and the method of food preparation.

Estimates of copper intake should include water copper content, the permitted upper concentration for copper in drinking water being 2 mg/L. The recommended intake in the first 6 months of life is 80 mg/kg/day. Thus, dietary copper intake far exceeds the trace amounts required.

Approximately 10% of dietary copper is absorbed in the upper intestine and binds loosely to albumin, certain amino acids (histidine, cysteine and threonine) and peptides. Most of the ingested copper is taken up by the liver. The hepatic uptake of diet-derived copper appears to be an unsaturable, carrier-mediated, energy independent mechanism.

Specific pathways allow the intracellular trafficking and compartmentalization of copper, ensuring adequate cuproprotein synthesis while avoiding cellular toxicity. After uptake by hepatocytes, copper is bound to metallothionein, a cytosolic, low molecular weight, cysteine-rich, metal binding protein. The copper stored in metallothionein can be donated to other proteins, either following degradation in lysosomes or by exchange via a glutathione (GSH) complex.

Biliary excretion is the only mechanism for copper elimination, and the amount of copper excreted in the bile is directly proportional to the size of the hepatic copper pool. Trafficking of copper in hepatocytes is complex and involves several transport proteins: the copper transporter 1 (Ctr1) transports copper with high affinity in a metal-specific, saturable fashion at the hepatocyte plasma subcellular localization rather than on its concentration in the liver.

Metallothionein-bound copper is non-toxic. Several metals including zinc can induce metallothionein synthesis.