Role of p38 Mapk in Development of Acute Hepatic Injury in Long-Evans Cinnamon (LEC) Rats, an Animal Model of Human Wilson's Disease

The Long-Evans Cinnamon (LEC) rat, an animal model of human Wilson's disease, spontaneously develops fulminant hepatitis associated with severe jaundice at about 4 months of age. In this study, we examined the changes in gene expression during progression of acute hepatic injury. When levels of gene expression in the liver of LEC rats at 13 weeks of age were compared to those in rats at 4 weeks of age using oligonucleotide arrays, 1,620 genes out of 7,700 genes analyzed showed more than 2-fold differences. Expression levels of 11 of 29 genes related to stress-activating protein kinase (SAPK) changed by more than 2-fold in the liver of LEC rats, but none of the SAPK-related genes showed changes in expression levels in the liver of control rats. Activity of p38 mapk in the liver of LEC rats at 13 weeks of age was about 8.1-fold higher than that in rats at 4 weeks of age. When LEC rats were administered SB203580, a p38 mapk-specific inhibitor, by s.c. injection twice a week from 10 to 13 weeks of age, activities of p38 mapk in the liver, activities of AST and ALT and concentrations of bilirubin in sera of rats administered SB203580 significantly decreased compared to those in rats not administered. These results showed that the increase in activities of p38 mapk was related to the occurrence of acute hepatic injury in LEC rats.