Pathogenesis of mallory body formation: studies using the drug-primed mouse model

Mallory bodies (MB) are formed in preneoplastic foci in the drug primed mouse model. These foci expand when the drug is refed. To better understand this phenotypic change in hepatocytes, the livers response to refeeding the drug was studied for transcriptional and post-translational changes. The post-translational change, hyperphosphorylation of MBs, was associated with changes in gene expression and activation of transcription regulation factors. Hyperphosphorylation of MBs appeared on the second day of refeeding the drug, the same time interval when MB formation began. Prior studies using this model showed an increase in the mitotic index and an increase in cytokeratin proteins at this time interval. In the present study, cytokeratin mRNA increased significantly, compared to the 0 day base line. Likewise, c-jun mRNA increased significantly at the same time interval. Previous studies on mice fed the drug for 5 months showed a significant increase in c-fos mRNA. The binding activity of AP-1 consensus oligonucleotide was significantly increased on the 5th day of refeeding. Taken together, the data support the conclusion that the MB phenotype change expands as the result of a response to stimulation of liver cell proliferation. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.