Rearrangement of the hepatocyte cytoskeleton after toxic damage: involution, dispersal and peripheral accumulation of Mallory body material after drug withdrawal.

Large cytoplasmic aggregates (Mallory bodies) containing randomly arranged 10 to 20 nm thick filaments are characteristic structures of hepatocytes in certain liver diseases, especially alcoholic hepatitis of man and griseofulvin intoxication of mouse. Biochemical and immunological studies have shown that such Mallory bodies contain structural proteins related to the cytokeratins present in epithelial cells of various kinds, normal hepatocytes included. We have studied the mode of reorganization of the hepatocyte cytoskeleton during involution of Mallory bodies experimentally induced in mice by prolonged griseofulvin feeding after withdrawal of the drug, using immunofluorescence microscopy and electron microscopy. Dispersal of Mallory bodies into small granules accumulating in the hepatocyte periphery is a characteristic feature of Mallory body involution. Dispersed heaps of Mallory body material are seen in hepatocyte cortices at lateral (hepatocyte-to-hepatocyte) as well as at sinusoidal cell surfaces. Mallory body material dispersed to the cell periphery exhibits a filamentous ultrastructure an often shows conspicuous associations with desmosomes. Three different types of desmosome complexes can be discriminated in livers of mice allowed to recover from the intoxication: (i) desmosomes with normally looking bundles of tonofilaments; (ii) desmosomes associated with Mallory body filaments but few, if any, tono-filaments; and (iii) desmosomes lacking tonofilaments as well as Mallory body filaments. The associations between Mallory body filaments and desmosomes during Mallory body involution further strengthen the relationship between Mallory body filaments and tonofilaments. The observations suggest that Mallory body material, at least in part, may be utilized for rearrangement of the hepatocyte cytoskeleton, especially tonofilament-desmosome complexes.