EXPERIMENTAL MALLORY BODY FORMATION IS ACCOMPANIED BY MODULATION OF THE EXPRESSION OF MULTIDRUG-RESISTANCE GENES AND THEIR PRODUCTS

Mallory bodies (MBs) are characteristic morphological features of alco holic hepatitis and are also found in other chronic liver disorders an d hepatocellular neoplasms, MBs can be produced in mouse liver by chro nic administration of the porphyrinogenic drugs griseofulvin (GF) and 3,5-diethoxy-carbonyl-1,4-dihydrocollidine (DDC). The mechanisms causi ng the formation of MBs are poorly understood, and the significance of MB formation during the course of liver disease remains unclear, We i nvestigated the relationship between the mechanisms underlying the for mation of MBs and the regulation of multidrug resistance (mdr) genes a nd their products, the P-glycoproteins (Pgp), Immunofluorescence micro scopy using the monoclonal antibody C219 revealed an increase of Pgp e xpression in almost all hepatocytes after 3 to 8 days of feeding mice DDC- and GF-containing diets. However, after approximately 4 weeks of DDC and approximately 8 weeks of GF feeding, when the first small MBs appeared and loosening and diminution of keratin intermediate filament (KIF) cytoskeleton occurred in some hepatocytes, a decrease or loss o f Pgp staining in affected hepatocytes was observed. After feeding mic e DDC for 6 week and GF for 12 weeks, many hepatocytes contained MBs a nd displayed a disruption of the immunohistochemically demonstrable KI F meshwork Double immunofluorescence microscopy with the keratin polyc lonal antibody and the mab C219 at this time point revealed a complete loss of Pgp staining in affected cells, although remaining hepatocyte s with unaltered KIF meshwork showed a strong reaction with the C219 a ntibody, Northern blot analyses revealed a significant increase of mdr 2 mRNA and, to a lesser extent, of mdr1a mRNA in the Livers of DDC- an d GF-fed animals.