Cellular mechanisms of toxicity and tolerance in the copper-loaded rat. II. Pathogenesis of copper toxicity in the liver.

The distribution of copper has been studied in the liver of the copper-loaded rat at the ultrastructural level by X-ray electron probe microanalysis in order to clarify the pathogenesis of copper-induced damage. Male rats fed a high copper diet (1500 ppm) for 16 weeks were killed at intervals; their livers were removed and fixed in 4% paraformaldehyde and 2% glutaraldehyde for electron microscopy and were analyzed for copper by AA spectrophotometry. Three different forms of lysosomes were identified with respect to their morphology and X-ray emission profiles: Type I lysosomes appeared early and contained iron and zinc in addition to markedly elevated copper peaks, whereas later appearing Type II lysosomes included sulfur and phosphorus in addition to copper. Type III lysosomes were associated with the recovery period and contained much reduced elemental residue. Degenerative changes were not observed in any of the three types of lysosomes. Copper and other elemental residues, including sulfur, were also identified within the hepatic parenchymal cell nuclei and by contrast were associated with irreversible nuclear damage. Nuclear copper is directly injurious to this organelle and responsible for the subsequent cell death whereas copper contained within lysosomes is apparently innocuous.