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

Mallory bodies (MB) are formed in preneoplastic foci in the drug primed mou se model. These foci expand when the drug is refed. To better understand th is phenotypic change in hepatocytes, the livers response to refeeding the d rug was studied for transcriptional and post-translational changes. The pos t-translational change, hyperphosphorylation of MBs, was associated with ch anges in gene expression and activation of transcription regulation factors . Hyperphosphorylation of MBs appeared on the second day of refeeding the d rug, the same time interval when MB formation began. Prior studies using th is model showed an increase in the mitotic index and an increase in cytoker atin 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 respons e to stimulation of liver cell proliferation. (C) 1998 Elsevier Science Ire land Ltd. All rights reserved.