Induction and progression of cholangiofibrosis in rat liver injured by oral administration of furan.
Cholangiofibrosis is a structural anomaly that precedes the development of cholangiocarcinoma in some rodent models. In this article, the authors examine the contribution of the epithelial and mesenchymal cells in the pathogenesis of this complex lesion. Furan was administered to rats by gavage in corn oil at 30 mg/kg b.w. (five daily doses per week) and livers were sampled between eight hr to three months. Characteristically the administration of furan caused centrilobular injury, and restoration was accomplished by proliferation of hepatocytes. Some areas of the liver were, however, more severely affected, and here, injury extended into portal and capsular areas, which resulted in a rapid proliferation of ductular cells that extended into the parenchyma accompanied by a subtype of liver fibroblasts. These ductules either differentiated into hepatocytes, with loss of the associated fibroblasts, or progressed to form tortuous ductular structures that replaced much of the parenchyma, leading to cholangiofibrosis. Although it is unclear what determines the difference in the hepatic response, a loss of micro-environmental cues that instigate hepatocyte differentiation and termination of the hepatocyte stem cell repair response may be perturbed by continual furan administration that results in an irreversible expansile lesion that may mimic the features of cholangiocarcinoma.
Hickling
K C
KC
Safety Assessment, AstraZeneca R&D Charnwood, Loughborough, United Kingdom. Kevin.Hickling@Astrazeneca.com
Hitchcock
J M
JM
Chipman
J K
JK
Hammond
T G
TG
Evans
J G
JG
D000284:Administration, Oral; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000473:pathology*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D018450:Disease Progression; D004847:Epithelial Cells; D005663:Furans / Q000008:administration & dosage / Q000633:toxicity*; D022781:Hepatocytes / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D005663:Furans; C039281:furan