Intracellular distribution of copper in the liver of normal and copper loaded sheep

Thirteen sheep were dosed repeatedly with copper sulphate in order to induce chronic copper poisoning. Twelve similar sheep acted as controls. Three dosed sheep were killed before haemolysis, six at haemolysis and four after cessation of the haemolytic crisis. The subcellular distribution of Cu, Zn, Fe and lysosomal marker enzymes was investigated in the livers of normal sheep and copper loaded sheep. In control sheep the highest concentration of Cu was in the nuclear fraction. Copper loading increased the concentration of Cu in all fractions. The proportion of Cu in the nuclear fraction continued to increase while that in the heavy mitochondrial fraction decreased. Significant increase in lysosomal enzymes along with electron microscopic studies on pellets of fractions indicated: (a) proliferation of lysosomes, (b) possible localisation of Cu in lysosomes, and (c) sedimentation of the denser lysosomes on N and MH fractions in test sheep with the majority being in the N fraction. Thus the increase in Cu observed in the N fraction is at least partly due to the storage of Cu by lysosomes which sediment with the heavier nuclei. The excessive deposition of Cu in lysosomes and nuclei may lead to cell damage. With increase in hepatic Cu concentration the proportion of Zn and Fe in the cytosol decreased.