BILE-DUCT OBSTRUCTION IS NOT A PREREQUISITE FOR TYPE BILIARY EPITHELIAL-CELL HYPERPLASIA

Biliary obstruction, produced by common bile duct ligation or alpha-na phthylisothiocyanate (ANIT) treatment in rats, has been associated wit h the development of type I biliary epithelial cell (BEC) hyperplasia. However, the exact mechanism(s) by which bile duct obstruction lead(s ) to this proliferative lesion are not clear. The present studies were designed to determine if cholestasis, in the absence of biliary obstr uction, would result in type I BEC hyperplasia. Male Sprague-Dawley ra ts were given a single oral dose of 150 mg/kg ANIT or iv doses of estr adiol glucuronide (E-2-17G; 21 mu mol/kg/h for 48 h) to produce obstru ctive and non-obstructive cholestasis, respectively. E-2-17G treatment resulted in cholestasis that was comparable in extent and duration to that observed following ANIT treatment. E-2-17G and ANIT treatments p roduced comparable increases in serum bile acids (55- to 60-fold) and activities of ALT (36- to 38-fold), ALP (4- to 5-fold), and 5'-nucteot idase (7- to 11-fold), respectively, compared to controls. Both ANIT a nd E-2-17G also increased serum bilirubin concentrations. ANIT treatme nt resulted in significant increases in biliary glucose concentrations that were associated with BEC damage/necrosis and obstruction of the bile duct lumen. Conversely, no evidence of BEC damage was observed in E-2-17G-treated rats. Nonetheless, BEC hyperplasia was observed in th e majority of rats following treatment with either ANIT or E-2-17G, as sessed by light microscopy and by BrdU immunohistochemistry. These dat a indicate that E-2-17G treatment produces nonobstructive cholestasis and type I BEC hyperplasia, suggesting that biliary obstruction is not a prerequisite for type I BEC hyperplasia in rats. Differences in the time of onset of hyperplasia were observed: hyperplasia was noted imm ediately following 48 h of E-2-17G-induced cholestasis but occurred se veral days after ANIT-induced cholestasis had subsided. Since the magn itude/duration of cholestasis was similar in the two models but the te mporal association between cholestasis and type I BEC hyperplasia were different, these data suggest that the proliferative stimulus may be different in the two models and that E-2-17G-induced type I BEC hyperp lasia may not be attributed solely to cholestasis. (C) 1998 Academic P ress.