The main and best established points about how mammalian Cu homeostasis occurs through a balance between absorption, transport and excretion, and the important roles of secretions are summarized in Figure 1. The figure depicts the amounts of Cu entering the digestive tract from various sources and how they travel from the intestine to key organs (like liver and kidney) and the rest of the organism, as well as how Cu is excreted. Values indicated are average mg Cu per day, based on the current and earlier literature, as previously discussed. Starting with Cu in food and drink entering the mouth (top left; “Diet”), as well as that in salivary, gastric, biliary and pancreatic secretions, plus some Cu from the intestinal mucosal cells of the small intestine, provide Cu to the GI tract. Most of that is absorbed in the duodenum of the small intestine.

Transfer of absorbed Cu from the intestinal cells to the blood is accomplished mainly by the Cu ATPase (ATP7A). Based upon tracer studies with radioactive Cu, Cu that enters the hepatic portal circulation binds tightly to proteins that compose the exchangeable Cu pool of the blood plasma, which consists mainly of albumin and alpha-2-macroglobulin (transcuprein), but may include other protein or non-protein components. The bulk of this Cu then first enters cells of the liver and partly also those of the kidney (Figure 2), where Cu is supplied to endogenous Cu-dependent proteins via various chaperones (ATOX1, CCS, Cox17). Most travels to the transmembrane Cu “pump”, ATP7B, in the trans Golgi network, from where a significant portion is incorporated into ceruloplasmin (Cp) for secretion into the blood via exocytosis, where it joins Cu on albumin and transcuprein/macroglobulin for delivery to cells in other organs all over the body (including the intestine). Another portion of Cp interacts with Fe (orange section of the diagram) to facilitate Fe release and transport on its blood carrier, transferrin. Hephaestin (Hp), a membrane-bound homolog of Cp, plays a similar role in Fe release from enterocytes to the blood. Excess Cu in the liver cells finds its way into the bile after entering the bile canaliculi, with the help of ATP7B and the endo-lysosomal compartment (see Figure 4). Most excretion of Cu is via the bile, as biliary Cu is not as readily re-absorbed, and so ends up in the feces. Cells regularly sloughed off the intestinal mucosa and degraded in the large intestine may also contribute to fecal excretion. Normally, only a small amount of Cu is excreted in the urine, which probably derives not only from tubular secretions but also the filtration of blood plasma. However, urinary secretion markedly increases when biliary secretion is compromised, leading to increases in small Cu carriers (SCC) in blood plasma that greatly increase levels of SCC in the urine. A great deal is still unknown about the additional forms of Cu that may be involved in its flow, especially through various secretory pathways leading to the blood, bile and urine, and the contributions of these processes and components to mammalian Cu homeostasis.