Copper overload

In mammals, as in yeast, several different metallothionein isoforms are known, each with a particular tissue distribution (Vasak and Hasler, 2000). Their synthesis is regulated at the level of transcription not only by copper (as well as the other divalent metal ions cadmium, mercury and zinc) but also by hormones, notably steroid hormones, that affect cellular differentiation. Intracellular copper accumulates in metallothionein in copper overload diseases, such as Wilson s disease, forming two distinct molecular forms one with 12 Cu(I) equivalents bound, in which all 20 thiolate ligands of the protein participate in metal binding the other with eight Cu(I)/ metallothionein a molecules, with between 12-14 cysteines involved in Cu(I) coordination (Pountney et ah, 1994). Although the role of specific metallothionein isoforms in zinc homeostasis and apoptosis is established, its primary function in copper metabolism remains enigmatic (Vasak and Hasler, 2000). 

At present, many natural and synthetic chelators have been studied as potential pharmacological agents for the treatment of iron or copper overload under various pathophysiological conditions. (The chelating activity of flavonoids was already discussed above and the application of chelators in thalassemia and some other pathologies is considered in Chapter 31.) There are specific thermodynamic demands to chelators to be efficient antioxidants [369], We will consider just several chelators of potential therapeutic importance. 

The amino acid histidine is used for the treatment of copper overload in Wilson s disease and forms a strong 1 2 complex (Fig. 27) (553). Copper-histidine therapy is also an efficient treatment for copper deficiency in Menkes disease (554). 

Myers, B.M., Prendergast, F.G., Holman, R., Kuntz, SJM., LaRusso, NX". Alterations in hepatocyte lysosomes in experimental hepatic copper overload in rats. Gastroenterology 1993 105 1814—1823... 

Copper poisoning can cause hepatic cirrhosis in Wilson s disease (SEDA-21, 234) (27), bnt no cases appear to be known in which this resulted from medicinal exposure. Apart from Wilson s disease and Menkes disease, much attention has been given to copper-associated liver disease in infancy and childhood, in which excessive dietary copper overload and a genetic predisposition can lead to high hver copper concentrations and progressive liver disease (28). 

A 34-year-old woman developed jaundice 11 days after starting to take omeprazole for ulcer dyspepsia (19). Her hver function tests suggested acute hepatitis with large rises in transaminases. Investigations excluded virus infections, autoimmune disorders, copper overload, and alphai antitrypsin deficiency. On withdrawal of omeprazole, the transaminases gradually normalized. 

Golgi apparatus, endoplasmic reticulum, and plasma membrane, and are responsible for copper transport. A mutation of this gene is responsible for Wilson s disease. Copper is poorly incorporated into the ceruloplasmin when translocase is defective. Metal ions are also sequestrated into lyso-somes, especially under conditions of copper overload (Mohan etal. 1995). The liver, which is the only true storage site that may be mobilized in the case of a negative copper balance, retains 20% of body copper. Muscles and brain account for 40% and 20%, respectively, but this copper is not available to assess in copper balance maintenance. A carrier-mediated facilitated diffusion system for uptake of copper complexes, amino acids and small peptides was identified in the rat hypothalamus (Harttler and Barnea 1988). Copper transport into the bile takes place in association with the biliary excretion of glutathione (Freedman etal. 1989). 

The highly homologous Wilson disease P-type ATPase (ATP7b) and the Menkes s P-type ATPase (ATP7a) differ only in their tissue expression and both function to move copper from one intracellular compartment to another. The ATP7a is predominantly located in the placenta, blood-brain barrier, and gastrointestinal tract and hence any mutation in the Menkes s P-type ATPase results in a copper deficiency in the fetus, brain, and tissues. In contrast, the Wilson s disease P-type ATPase is expressed in the liver and mutations in this culminate in profound copper overload of the liver because of the inability to shuttle copper into the trans golgi network for incorporation into ceruloplasmin. The excess copper is stored in the liver and eventually leaks out in the serum where it is deposited within sensitive tissues the eye and brain. The psychiatric... 

Deficiency of sulfur amino acids can result in reduced CoA synthesis likewise copper overload can (by interfering with sulfur amino acid function) also reduce CoA synthesis. 

---