Mechanisms for biological control of metals and participation of metal-binding proteins : disordered copper metabolism in LEC rats.

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Our approach can be described under several subheadings as following : (i) Process of normal accumulation of copper in LEC rats leading to and following acute hepatitis, (ii) Selective transfer of copper from metallothionein to copper-binding enzymes in LEC rats, (iii) Selective removal of copper bound to metallothionein by tetrathiomolybdate and recovery from acute hepatitis, and (iv) Enhanced induction of metallothionein synthesis in the liver of LEC rats.Our experiments revealed that copper accumulates in the liver of LEC rats in a form bound to metallothionein up to the limits of liver's capacity to synthesize this protein. Then copper not bound to metallothionein starts to appear in free form in liver cells and signs of acute hepatitis (jaundice) begin to appear. Copper liberated from the copper-metallothionein in liver is detected in the blood stream and is sequestered by the kidney. Although, this copper is not incorporated in ceruloplasmin (a specific copper-dependent protein) and apo-ceruloplasmin appears in the serum of LEC rats, the metal can be utilized by the copper, zinc-superoxide dismutase. The phenomenon can be explained by a direct and selective transfer of copper from metallothionein to apo-superoxide dismutase. Copper present in liver, bound to metallothionein was removed selectively by tetrathiomolybdate and the mechanisms, including the formation of molybdenum-copper-sulfur complexes, were proposed. LEC rats can be cured from the acute hepatitis by treatment with tetrathiomolybdate.Abnormal accumulation of copper in LEC rats is now explained by the lack of copper-binding liver ATPase, which cause the efflux of copper from this organ, However, our results suggest that metallothionein synthesis is enhanced even in the hepatocytes derived from the LEC rats after removing copper and lowering the metallothionein mRNA levels to normal values, indicating that metallothionein is overexpressed in LEC rats selectively by copper.