Association of copper to metallothionein in hepatic lysosomes of Long-Evans cinnamon (LEC) rats during the development of hepatitis [se e comments].
BACKGROUND
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 still unclear.


RESULTS
In liver cytosol, copper levels were highest just before the onset of hepatitis and declined thereafter. In cytosol, total copper was bound to metallothionein (MT). Considerable amounts of both copper and iron accumulated in lysosomes with increasing age and development of liver damage. Lysosomal levels of presumably reactive non-MT-bound copper were increased. In severely affected livers, large amounts of copper were associated with insoluble material of high density which, upon ultrastructural information, was found to be derived from the lysosomes of Kupffer cells. This copper-rich material is considered to consist of polymeric degradation products of copper-MT.


CONCLUSIONS
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 directly or through stimulation of these cells.
Klein
D
D
Institute of Toxicology and Environmental Hygiene, Technical University Munich, Germany.
Lichtmannegger
J
J
Heinzmann
U
U
Müller-Höcker
J
J
Michaelsen
S
S
Summer
K H
KH
D000818:Animals; D003300:Copper / Q000032:analysis / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006520:Hepatitis, Animal / Q000378:metabolism* / Q000473:pathology; D006527:Hepatolenticular Degeneration / Q000378:metabolism; D006801:Humans; D007728:Kupffer Cells / Q000473:pathology / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008668:Metallothionein / Q000032:analysis / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000648:ultrastructure; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar
D003300:Copper; D008668:Metallothionein