Early changes in bile duct lining cells and hepatocytes in rats treated with alpha-naphthylisothiocyanate.

Morphological changes in bile duct lining cells precede morphological changes in hepatocytes in rats treated with 300 mg/kg body wt of alpha-naphthylisothiocyanate (ANIT). Four hours after dosing, electron microscopy showed dilation of bile ducts, loss of microvilli from bile duct epithelial cells, and an apparent opening of the tight junctions between some bile duct epithelial cells. These changes were more pronounced after 6 hr and there was in some bile duct lining cells detachment of the nuclear membrane and vacuolation of the endoplasmic reticulum. Light microscopy 6 hr after treatment with ANIT showed some portal edema and loss of gamma-glutamyl transpeptidase activity from the bile duct lining cells. By 8 hr after treatment many ducts showed clear-cut damage, with bile plugs forming and cells exfoliating into the ducts. Twenty-four hours after treatment the majority of bile ducts were destroyed but by 48 hr there was some evidence of regeneration. No tissue changes were seen at the light microscopy level in the liver parenchymal cells 4, 6, or 8 hr after treatment. At the ultrastructural level some alterations in the tight junctions between hepatocytes were seen 6 hr after treatment. No other changes were observed before this time point. By 24 hr after treatment there was focal necrosis in the parenchyma. Assay of gamma-glutamyl transpeptidase and albumin in bile gave results consistent with the histochemical evidence for the loss of activity from bile duct lining cells and for weakening of the tight junctions between hepatocytes.