Selective Removal of Copper Bound to Metallothionein

2.2.1. Copper Accumulating in the Form Bound to Metallothionein by the Defective ATP7B

The concentration of Cu in the body is maintained homeostatically within a certain level. However, in the liver of Wilson's disease patients and its animal model, LEC rats, Cu accumulates in a form bound to MT owing to the mutation of the Cu-binding ATPase for the efflux of Cu (ATP7B) that is expressed in the liver (5-7,14). ATP7B is responsible for the transport of Cu in the cytoplasm into the Golgi apparatus (26-28) and also into the bile (29). In the normal functioning body, the Cu transported into the Golgi apparatus is supplied to ceruloplasmin (CP) and secreted into the blood-

Metallothionein

Fig. 1. Production of monovalent Cu by metallothionein depending on Zn and Cu on metallothionein. Although Zn and Cu are coordinated with four (tetrahedral) and three (trigonal) thiol groups on MT, respectively, only two thiol groups are depicted for Zn and Cu to simplify the reaction in this figure.

Fig. 1. Production of monovalent Cu by metallothionein depending on Zn and Cu on metallothionein. Although Zn and Cu are coordinated with four (tetrahedral) and three (trigonal) thiol groups on MT, respectively, only two thiol groups are depicted for Zn and Cu to simplify the reaction in this figure.

Atp7b Molcule
Fig. 2. Production of reactive oxygen species by one electron reduction of oxygen molecules.

stream in a form bound to CP. Excessive Cu is excreted into the bile, the chemical form of Cu transported into the bile being assumed to be cuprous ions as a result of the function of ATP7B. The schematic diagram for the role of ATP7B is shown in Fig. 3.

As ATP7B is not functioning genetically in the livers of patients with Wilson's disease and LEC rats, Cu is not transported into the Golgi apparatus and accumulates in the cytoplasm. Excessive accumulation of Cu is toxic to the body and the body induces the synthesis of MT to sequester the excess Cu in a nontoxic form, Cu,Zn-MT (15,16). As a result, Cu accumulates in the liver in the form bound to MT without showing toxic effects until it accumulates up to the limit of the capacity of MT synthesis (18-20).

In the normal subjects and rats without the defective ATP7B, the ATP7B is localized on the Golgi membrane and transports Cu from the cytoplasm into the Golgi apparatus under the certain concentration of Cu. However, when the concentration of Cu in the cytoplasm increases more than the certain level, ATP7B is translocated on the plasma membrane and exports Cu from the cytoplasm into the bile (28).

In Wilson's disease patients and LEC rats, the two major excretion routes for Cu through the transporter ATP7B are not functioning. As a result, Cu accumulates in the liver and induces the synthesis of MT, resulting in the accumulation of Cu,Zn-MT followed by Cu-MT.

Diagram Copper Transport Liver
Fig. 3. Schematic diagram for the transport of Cu into the Golgi apparatus and the bile by ATP7B.

2.2.2. How to Decrease the Concentration of Copper Accumulating in the Form Bound to Metallothionein

The concentration of Cu accumulating in the form bound to MT can be decreased either by reducing the intake of Cu or by removing the Cu accumulating in the liver. The former approach is possible by feeding diets and water of low Cu content, by competing the uptake/absorption of Cu with Zn (30,31), or by inhibiting the uptake/absorption of Cu by complexing with chelating agents, trientine, and D-penicillamine (31-34). The chelating agents may remove Cu not bound to CP in the bloodstream as well. However, the affinity of Cu to MT is greater than those of these chelating agents, and the Cu bound to MT in the liver cannot be removed. The former approach with diets of low Cu content may be possible for experimental animals but not practical for humans. The use of chelating agents is effective in retarding the onset of hepatitis (35). However, chelating agents are not powerful enough to remove Cu accumulating in the form bound to MT in the liver (36).

Contrary to the strategies mentioned earlier, the removal of Cu directly from MT seems to be more effective in reducing the concentration of Cu accumulating in the form bound to MT in the liver. This approach is possible only with the chelating agent, TTM (37). TTM was used to antagonize the toxicity of Cu based on the observations that Cu and molybdenum (Mo) form a complex in the presence of sulfur under anaerobic conditions in the gastrointestinal tract and that the availability of both metals becomes negligible by the complex formation in livestock (38).

The mechanisms underlying the complex formation between TTM and Cu and its application to the removal of Cu from the livers of patients of Wilson's disease and LEC rats are described in Chapter 5.

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    How to remove cu from animal?
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