BILIARY-EXCRETION OF COPPER, METALLOTHIONEIN, AND GLUTATHIONE INTO LONG-EVANS CINNAMON RATS - A CONVINCING ANIMAL-MODEL FOR WILSON DISEASE

Long-Evans Cinnamon (LEG) rats, characterized by a gross accumulation of hepatic Cu and the spontaneous onset of hepatitis, have been establ ished to be an animal model for Wilson disease. They were used to esti mate the relationships among copper (Cu), metallothionein (MT), and re duced glutathione (GSH) in biliary excretion in this study. Even thoug h a huge amount of MT existed in the LEC rat liver (5016 mu g/g liver) compared to that (63 mu g/g liver) of controls (Fischer rats), the bi liary excretion of MT (65 ng/ml bile) did not reflect the accumulated MT level in LEC rats. It seems likely that MT does not excrete intrins ically into the bile. Biliary excretion of Cu (0.17 mu g/ml) in LEC ra ts was significantly lower than that (0.57 mu g/ml) in Fischer rats. T he difference in biliary excretion of GSH between the two groups was s ignificant but slight. The reduced excretion of GSH into bile in LEC r ats may be due to increased hepatic gamma-glutamyltransferase but not to hepatic GSH levels. There were no differences in biliary potassium and inorganic phosphorous between the two groups. On the other hand, e xcretion of lysosomal enzymes such as beta-N-aeetylglucosaminidase int o bile was much lower in LEC rats (15.6 units/liter) than in controls (42.5 units/liter). The defective biliary excretion of Cu may be due t o impaired lysosomal exocytosis, rather than canalicular membrane impa irment. The LEC rat is very useful for research into the dynamics of m etal excretion via the hepatobiliary system. (C) 1995 Academic Press, Inc.