Disordered copper metabolism in LEC rats, an animal model of Wilson disease: roles of metallothionein.

Disordered copper (Cu) metabolism in LEC rats, an animal model of Wilson disease, was characterized by specifying Cu in the liver, bloodstream and kidneys during the accumulation process and at the onset of jaundice; Cu accumulates in the liver with age in a form bound to metallothionein (MT). Massive Cu is liberated from MT when Cu accumulates beyond the capacity of MT synthesis. Cu bound to MT is not supplied to ceruloplasmin (Cp) during its maturation process, while the metal is transferred to Cu,zinc (Zn)-superoxide dismutase (SOD) directly from MT. Cu ions not bound to MT are transferred to Cp and the holo-Cp is excreted into the bloodstream near and at the onset of jaundice. Cu accumulated in the liver in a form bound to MT is removed selectively by tetrathiomolybdate (TTM), and the animal at the beginning of the onset of jaundice recovers by the chelation therapy. Mechanisms of the removal reaction were proposed to involve formation of MT/TTM, Cu/TTM, and/or polymeric Cu/TTM complexes according to the stoichiometry of TTM to Cu. The Cu/TTM complex was assumed to be effluxed into the bloodstream and to bind specifically to albumin. TTM is taken up by the liver in accordance with the Cu content. The toxicity of Cu was explained by the active oxygen species produced in Cu-mediated reactions, and the participation of MT.