Hepatic lysosomal copper-thionein

In certain pathological and experimental conditions associated with hepatic copper overload, an important portion of the excess metal is bound to a copper-thionein and sequestered in hepatocellular lysosomes. The localization can be demonstrated visually by using histochemical and immunocytochemical stains and by extraction of the Cu-protein from particulate fractions of liver homogenates. The livers of Bedlington terriers affected by an inherited defect resulting in the accumulation of large quantities of copper display hepatocellular lysosomes which appear as dense, insoluble, copper-rich granules. Purification and solubilization of the fraction containing these granules yields a copper-thionein with little zinc, which displays homology with other known metallothioneins. Although the primary genetic defect which underlies the pathogenesis of this form of hepatic copper overload is still unknown, circumstantial evidence suggests that sequestration of the protein by lysosomes may be temporarily cytoprotective.