Induction and Progression of Cholangiofibrosis in Rat Liver Injured by Oral Administration of Furan

Abstract

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.

Functional and proliferative effects of repeated low‐dose oral administration of furan in rat liver

“…In rats administered relatively high doses of furan, it was recently shown that bile duct proliferation occurs in severely affected areas within the parenchyma, but not in regions where proliferation of surviving hepatocytes was apparently sufficient to replace necrotic cells [14]. Proliferating biliary ducts extended from the portal tracts into the injured parenchyma, where they started to differentiate into hepatocytes.…”

“…These observations suggest that proliferation of biliary cells in rats occurs secondary to hepatocyte damage as part of a repair process to compensate for the cell loss. In most severely injured areas, however, expanding ductal cells acquired an intestinal rather than hepatocellular phenotype prior to the appearance of intestinal metaplasia [14], suggesting that the normal repair process was perturbed.…”

“…In addition, previous work demonstrating a marked increase in 8-oxo-7,8-dihydro-2 0 -deoxyguanosine (8-oxo-dG) at sites associated with furaninduced hepatocyte necrosis [13] indicates that secondary oxidative DNA damage resulting from cytotoxicity and chronic inflammation -coupled with enhanced cell turnover -may contribute to furan carcinogenicity. When the dose level is sufficient to cause both centrilobular and periportal necrosis, this can lead to irrecoverable metaplasia and cholangiofibrosis which continues to expand, even after cessation of furan treatment, and is accompanied by a persistent chronic inflammatory infiltrate [14].…”

Hepatobiliary Toxicity of Furan: Identification of Furan Metabolites in Bile of Male F344/N Rats

“…However, whether or not membrane transporters represent furan target proteins remains to be established. Alternatively, it has been suggested that proliferative signals to biliary epithelial cells may arise due to hepatocyte damage as part of a portal bile ductular hepatocyte repair process that is activated when the capacity for adaptive repair is overwhelmed by high doses or sustained exposure to furan (Hickling et al, 2010). In summary, further investigations will be required to understand the cellular and functional consequences associated with furan-mediated protein damage and current work in our laboratory is focused on identifying critical target proteins that may play a causal role in the pathogenesis of furan-associated liver toxicity.…”

“…The molecular mechanism(s) underlying the hepatobiliary toxicity of furan are still poorly understood. A recent histological and immunocytochemical investigation provided evidence to suggest that cholangiofibrosis as a precursor lesion of cholangiocarcinoma arises from perturbation of a portal bile ductular hepatocyte repair process after irretrievable hepatocyte loss (Hickling et al, 2010). On the other hand, a study on the disposition of [ 14 C]furan in male F344 rats demonstrated that biliary excretion is a major route of elimination of furan (Burka et al, 1991), suggesting that damage to the bile duct epithelium may occur as a result of high concentrations of toxic furan metabolites in bile.…”