BILIARY EPITHELIAL-CELL PROLIFERATION FOLLOWING ALPHA-NAPHTHYLISOTHIOCYANATE (ANIT) TREATMENT - RELATIONSHIP TO BILE-DUCT OBSTRUCTION

These studies were designed to evaluate the importance of bile duct ob struction in the pathogenesis of alpha-naphthylisothiocyanate (ANIT)-i nduced biliary epithelial cell (BEC) hyperplasia in rats. Hepatobiliar y function and morphology were evaluated in adult male Sprague-Dawley rats 16, 24, 48, 72, 120, and 168 hr after a single oral dose of ANIT (0, 25, 75, or 150 mg/kg). After 75 or 150 mg/kg ANIT, multifocal bile duct obstruction was observed at 48 and 72 hr and preceded BEC hyperp lasia which occurred at 120 and 168 hr. BEC proliferation, reflected b y 5-bromo-2'-deoxyuridine (BrdU) incorporation, occurred at doses and at time points coinciding with BEC necrosis and/or bile duct obstructi on. In contrast, 25 mg/kg ANIT produced minimal BEC damage and no evid ence of bile duct obstruction or BEC hyperplasia. In a separate experi ment, BEC proliferation was evaluated following bile duct ligation or ANIT treatment (150 mg/kg). The onset and peak of BEC proliferation oc curred 24 and 48 hr, respectively, following bile duct obstruction res ulting from either ligation or ANIT treatment. Furthermore, BEC prolif eration occurred at all levels of the biliary tree in both bile duct-l igated and ANIT-treated rats. These data indicate that (a) dose-respon se curves for ANIT-induced bile duct obstruction and BEC hyperplasia a re similar; (b) ANIT-induced BEC proliferation and bile duct obstructi on precedes BEC hyperplasia; (c) BEC proliferation occurred at doses/t imepoints associated with BEC damage and bile duct obstruction; and (d ) once ANIT-induced bile duct obstruction occurs, the spatial and temp oral aspects of BEC proliferation are comparable to those following bi liary obstruction induced by bile duct ligation. Collectively, these d ata suggest that ANIT-induced BEC hyperplasia is secondary to intrahep atic bile duct obstruction. (C) 1995 Society of Toxicology.