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Although ceruloplasmin is known to be a copper-transporting protein, little is known about the biochemical mechanisms of copper incorporation into ceruloplasmin during the biosynthesis. We have examined various levels of ceruloplasmin biosynthesis in the Long-Evans Cinnamon (LEC) rat, which possesses a mutation causing the deficiency in serum ceruloplasmin activity associated with excess hepatic copper accumulation. Southern and Northern blot analyses revealed that the gene and mRNA encoding ceruloplasmin resided normally in LEC rat liver. Western blot analysis showed a normal level of ceruloplasmin in LEC rat serum. Following metabolic labeling of hepatocytes with 64Cu, no radioactive copper was detected in the ceruloplasmin fraction in LEC rat hepatocytes using Sephadex G-75 column chromatography, indicating that copper incorporation into ceruloplasmin is deficient in the LEC rat. Furthermore, LEC rat hepatocytes incubated with 64Cu also showed a reduction in the efficiency of copper transport from cytosolic to noncytosolic fractions and a reduced copper efflux from the hepatocytes, indicating that LEC rat hepatocytes possess an abnormality in copper metabolism. These results suggest that an abnormality of the copper delivery mechanism causes an inhibition of copper incorporation into the ceruloplasmin molecule in the liver, leading to the deficiency in serum ceruloplasmin activity in the LEC rat. In addition, this abnormality also seems to cause an inhibition of biliary copper excretion. The blocking of these two copper exclusion pathways is thought to lead to excess hepatic copper accumulation in the LEC rat. Thus, the LEC rat should be a good model for studying the biochemical process responsible for copper delivery.
Yamada et al. (Thu,) studied this question.