IMPAIRED BILIARY-EXCRETION OF COPPER AND LYSOSOMAL-ENZYMES IN LONG-EVANS CINNAMON RAT

Although impaired biliary excretion of copper through hepatocyte lysos omes has been postulated as a pathogenesis of Wilson's disease, direct evidence has been lacking. Our aim was to investigate the dynamics of biliary excretion of copper and lysosomal enzymes in the Long-Evans C innamon (LEC) rat, a recently established rodent model of Wilson's dis ease. Liver homogenate and bile were obtained from 12 week-old LEC rat s (n = 7), Long-Evans Agouti rats (n = 3) and Sprague-Dawley rats (n = 8) and analyzed for copper and lysosomal enzymes. Structural integrit y of hepatic lysosomes was assessed by the latency of N-acetyl-beta-gl ucosaminidase. Compared with the controls, LEC rats exhibited a 43-fol d increase in hepatic copper concentration (p < 0.001), a significant increase in hepatic activities of lysosomal enzymes (p < 0.001) and re duction of lysosomal latency (p < 0.05). In contrast, biliary excretio n of copper and lysosomal enzymes were significantly impaired in LEC r ats (p < 0.05). These results suggest a coupled alteration between cop per and lysosomal enzymes in both the liver and bile of LEC rats (i.e. , increase in liver and decrease in bile). Defective biliary excretion of copper via hepatocyte lysosomes may play a role in part in spontan eous copper accumulation in LEC rats.