title: Bile duct obstruction is not a prerequisite for type I biliary epithelial cell hyperplasia.
abstract: Biliary obstruction, produced by common bile duct ligation or alpha-naphthylisothiocyanate (ANIT) treatment in rats, has been associated with 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 obstruction, would result in type I BEC hyperplasia. Male Sprague-Dawley rats were given a single oral dose of 150 mg/kg ANIT or i.v. doses of estradiol glucuronide (E2-17G; 21 mumol/kg/h for 48 h) to produce obstructive and non-obstructive cholestasis, respectively. E2-17G treatment resulted in cholestasis that was comparable in extent and duration to that observed following ANIT treatment. E2-17G and ANIT treatments produced 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'-nucleotidase (7- to 11-fold), respectively, compared to controls. Both ANIT and E2-17G also increased serum bilirubin concentrations. ANIT treatment 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 E2-17G-treated rats. Nonetheless, BEC hyperplasia was observed in the majority of rats following treatment with either ANIT or E2-17G, assessed by light microscopy and by BrdU immunohistochemistry. These data indicate that E2-17G 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 immediately following 48 h of E2-17G-induced cholestasis but occurred several days after ANIT-induced cholestasis had subsided. Since the magnitude/duration of cholestasis was similar in the two models but the temporal 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 E2-17G-induced type I BEC hyperplasia may not be attributed solely to cholestasis.
authors.affiliation: Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Kossor
authors.forename: P C
authors.initials: PC
authors.lastname: Meunier
authors.forename: D M
authors.initials: DM
authors.lastname: Dulik
authors.forename: T B
authors.initials: TB
authors.lastname: Leonard
authors.forename: R S
authors.initials: RS
authors.lastname: Goldstein
mesh_terms: D015058:1-Naphthylisothiocyanate; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000473:pathology*; D002779:Cholestasis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D004847:Epithelial Cells / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001647:Bile Acids and Salts; D015058:1-Naphthylisothiocyanate; D005947:Glucose