MALLORY BODY INDUCTION IN DRUG-PRIMED MOUSE-LIVER

The aim of this study was to determine the various factors that are in volved in the induction of Mallory body (MB) formation. A model was de veloped where MB formation was induced by refeeding either of the drug s griseofulvin or diethyl -dihydro-1,4,6-trimethyl-3,5-pyridinedicarbo xylate (DDC), Mice were fed the drugs for 5 months, followed by withdr awal of the drugs for 1 month (drug-primed livers), The drugs were ref ed for 1, 3, 5, 7, or 11 days, Early MBs first appeared as small, enla rged aggregates of filaments in the perinuclear or pericanalicular loc ation on the third day of refeeding. Mature MBs appeared on the fifth day of refeeding, MBs reached maximum concentration on day 5 of refeed ing. Western blots showed a progressive increase in the cyto keratin p roteins (CK49 and CK55) and actin while refeeding the drugs, Liver cel l regeneration, as indicated by the percent of proliferating cell nucl ear antigen (PCNA)-positive nuclei, increased on the third day of refe eding, However, there was no correlation between the frequency of MBs and the percent of PCNA-positive nuclei, It is concluded that MB forma tion is not related to the liver cell regeneration response to injury but rather involves a separate regulation pathway, The MBs were heavil y ubiquitinated and were associated with increased ubiquitin-protein c onjugates as indicated by Western blotting, suggesting that ubiquitini zation of cytokeratin protein are involved in the formation of MB aggr egation.