Bile canalicular alterations in hepatocyte nodules induced by 3'-methyl-4-dimethylaminoazobenzene in the rat: morphological clues on their pathogenesis and relevance to the neoplastic process.

One characteristic change of hepatocyte plasma membrane in chemically induced nodules of rat liver is the spreading over on the whole cell surface of proteins normally associated with the canalicular domain. However, these proteins may present comparable altered patterns of membrane distribution in non-neoplastic situations, e.g. in cholestatic states. Consequently, the significance of an abnormal membrane distribution of canalicular proteins in hepatocyte nodules and its possible relevance to the neoplastic process remain to be clarified. We have therefore performed an ultrastructural study of bile canalicular alterations in the hepatocyte nodules induced by 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB), in an attempt to gain some insight on their pathogenesis. We actually observed frequent bile canalicular changes in hepatocyte nodules from 10 to 16 weeks after the beginning of 3'-Me-DAB administration. These changes correlated with the rearrangements in hepatocyte architecture occurring at this stage of the neoplastic process, corresponding to the so-called pseudo-acinar structures and disorganized plates. In pseudo-acinar structures, hepatocytes were arranged in a tubular manner around dilated bile canaliculi. In this situation, bile canaliculi have lost many of their normal features and closely resemble ductular lumina. In disorganized plates, hepatocyte plates were thickened and irregularly branched. In this situation, bile canaliculi presented striking deviations from the normal, including: (i) dilatation and distortion, (ii) lesions of canalicular membrane (loss of microvilli, formation of blebs) and (iii) alterations in the pericanalicular cytoskeletal network. Most of these morphological abnormalities closely resembled those found in cholestatic states. Two pathogenetic mechanisms may be postulated to explain the cholestatic-like effect of 3'-Me-DAB: (i) a direct cellular injury caused by the carcinogen or (ii) an indirect consequence of the tissular rearrangements characteristic of disorganized plates. Our morphological results suggest that the phenotypic alterations of bile canaliculi induced by 3'-Me-DAB are not specific for the neoplastic process. They are likely to correspond to an impairment in the biogenesis of the canalicular membrane and/or in the maintenance of its integrity.