Mechanism underlying the selective removal of copper accumulating in the liver of LEC rats and development of the therapy for Wilson disease

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Wilson disease is caused by an abnormal accumulation of copper (Cu) in the liver owing to the inherited defect in Cu metabolism, and the Cu accumulates in the form bound to metallothionein (MT), Cu,Zn-MT. When Cu accumulates more than the biosynthetic capacity of MT, Cu-MT without Zn starts to work as a prooxidant and causes acute hepatitis. This mechanism was revealed by the speciation study of Cu in the liver, bloodstream, kidneys and urine.Cu accumulating in the liver has to be lowered in the therapy of Wilson disease either by i) feeding diets of low Cu content, ii) lowering the absorption at the gastro-intestinal tract or iii) removing Cu from Cu, Zn-MT in the liver. In the present study, the third approach was examined. Based on the complex formation between Cu, Mo and S, tetrathiomolybdate (TTM) was used to remove Cu in the liver of LEC rats, an animal model of Wilson disease. Precise mechanisms underlying the reaction between TTM and Cu bound to MT and underlying the removal of Cu from liver have been presented. TTM is specific not only to Cu among various metals but also to Cu bound to MT.The selective removal of Cu by TTM was demonstrated in vivo, and it was also shown that the Cu removed from the liver does not redistribute to other organs. The Cu removed from MT is effluxed into bile and bloodstream in the form of the Cu/TTM complex, and then excreted into feces but not into urine.As side-effects, it was shown that excessive treatment with TTM causes a severe Cu deficiency, and that sulfide ions produced by hydrolysis under acidic conditions affect acutely liver function. As a result, it has been recommended to administer TTM as a single or several injections but not repeatedly to avoid the side-effects due to overdose.