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 obstruction in the pathogenesis of alpha-naphthylisothiocyanate (ANIT)-induced biliary epithelial cell (BEC) hyperplasia in rats. Hepatobiliary 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 hyperplasia which occurred at 120 and 168 hr. BEC proliferation, reflected by 5-bromo-2'-deoxyuridine (BrdU) incorporation, occurred at doses and at time points coinciding with BEC necrosis and/or bile duct obstruction. In contrast, 25 mg/kg ANIT produced minimal BEC damage and no evidence of bile duct obstruction or BEC hyperplasia. In a separate experiment, BEC proliferation was evaluated following bile duct ligation or ANIT treatment (150 mg/kg). The onset and peak of BEC proliferation occurred 24 and 48 hr, respectively, following bile duct obstruction resulting from either ligation or ANIT treatment. Furthermore, BEC proliferation occurred at all levels of the biliary tree in both bile duct-ligated and ANIT-treated rats. These data indicate that (a) dose-response curves for ANIT-induced bile duct obstruction and BEC hyperplasia are similar; (b) ANIT-induced BEC proliferation and bile duct obstruction precedes BEC hyperplasia; (c) BEC proliferation occurred at doses/timepoints associated with BEC damage and bile duct obstruction; and (d) once ANIT-induced bile duct obstruction occurs, the spatial and temporal aspects of BEC proliferation are comparable to those following biliary obstruction induced by bile duct ligation. Collectively, these data suggest that ANIT-induced BEC hyperplasia is secondary to intrahepatic bile duct obstruction.
Kossor
D C
DC
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Goldstein
R S
RS
Ngo
W
W
DeNicola
D B
DB
Leonard
T B
TB
Dulik
D M
DM
Meunier
P C
PC
D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000502:physiology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects* / Q000473:pathology; D001663:Bilirubin / Q000097:blood; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D006965:Hyperplasia / Q000139:chemically induced; D007700:Kinetics; D008099:Liver / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D015058:1-Naphthylisothiocyanate; D001973:Bromodeoxyuridine; D001663:Bilirubin