Fate of copper and metallothionein in the liver of LEC rats

The Long-Evans cinnamon (LEC) rat has a mutation homologous to the human Wilson’s disease gene leading to copper induced hepatotoxicity. The mechanism of how excess copper damages the liver or what chemical form of copper is toxic is yet unclear. In liver cytosol copper levels are highest just before the onset of hepatitis and decline thereafter. In this compartment total copper was bound to metallothionein (MT). In lysosomes both copper and iron accumulate with increasing age and development of liver damage and considerable amounts of non MT-bound copper are present. In severely affected livers, large amounts of copper are associated with insoluble material of high density, which upon ultrastructural information, is derived from lysosomes of Kupffer cells. This copper-rich material is considered to consist of polymers of degradation products of copper-MT. We suggest that chronic copper toxicity in LEC rats involves the uptake of copper-loaded MT into lysosomes where it is incompletely degraded and polymerizes to an insoluble material containing reactive copper. This copper together with iron initiates lysosomal lipid peroxidation leading to hepatocyte necrosis. Subsequent to phagocytosis by Kupffer cells the reactive copper may amplify liver damage either direct or through stimulation of these cells.