Bile Duct Obstruction Is not a Prerequisite for Type I Biliary Epithelial Cell Hyperplasia

Kossor, David C.; Meunier, Paul C.; Dulik, Deanne M.; Leonard, Thomas B.; Goldstein, Robin S.

doi:10.1006/taap.1998.8507

Cited by 13 publications

(9 citation statements)

References 26 publications

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“…The identity of the proliferating cell type responsible for bile duct epithelial cell hyperplasia is somewhat controversial with hepatocytes, putative stem cells, and the pre-existing biliary epithelium all being candidates. 12,13,22,23,33,34 A number of in situ and in vitro studies support the conclusion that after bile duct ligation cholangiocytes most likely arise from different portions of the intrahepatic biliary tree and are morphologically and functionally similar to the subpopulation of cholangiocytes obtained from normal rat liver and do not acquire phenotypes of hepatocyte lineage. 14,22,24,33 Studies in the rat have shown that the pre-existing biliary epithelium is the source of proliferating bile duct cells and that bile Figure 6.…”

Section: Discussionmentioning

confidence: 91%

“…19 -22,32 Thus the pathogenesis of ANIT-induced cholestasis is biphasic; the onset of cholestasis is associated with changes in hepatocanalicular function, whereas bile duct epithelial cell proliferation follows later. 20,22,23 Continuous ANIT feeding is characterized by the development of time-and dose-dependent ductular hyperplasia. 21,24 Typical ductular hyperplasia produced by either ANIT feeding or common bile duct ligation results in cholangiocyte proliferation confined to the portal areas.…”

Section: Discussionmentioning

confidence: 99%

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Quantitative Assessment of the Rat Intrahepatic Biliary System by Three-Dimensional Reconstruction

Masyuk

Ritman

LaRusso

2001

The American Journal of Pathology

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The anatomical details of the biliary tree architecture of normal rats and rats in whom selective proliferation was induced by feeding ␣-naphthylisothiocyanate (ANIT) were reconstructed in three dimension using a microscopic-computed tomography scanner. The intrahepatic biliary tree was filled with a silicone polymer through the common bile duct and each liver lobe embedded in Bioplastic; specimens were then scanned by a microscopic-computed tomography scanner and modified Feldkamp cone beam backprojection algorithm applied to generate three-dimensional images. Quantitative analysis of bile duct geometry was performed using a customized software program. The diameter of the bile duct segments of normal and ANIT-fed rats progressively decreased with increasing length of the biliary tree. Diameter of bile ducts from ANIT-fed rats (range, 21 to 264 m) was similar to that of normal rats (22 to 279 m). In contrast, the number of bile duct segments along the major branch reproducibly doubled, the length of the bile duct segments decreased twofold, and the length of the biliary tree remained unchanged after ANIT feeding. Moreover, the total volume of the biliary tree of ANIT-fed rats was significantly greater (855 l) than in normal rats (47 l). Compared with normal rats, the total surface area of the biliary tree increased 26 times after ANIT-induced bile duct proliferation. Taken together, these observations quantitate the anatomical remodeling after selective cholangiocyte proliferation and strongly suggest that the proliferative process involves sprouting of new side branches. Our results may be relevant to the mechanisms by which ducts proliferate in response to hepatic injury and to the hypercholeresis that occurs after experimentally induced bile duct proliferation.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Quantitative Assessment of the Rat Intrahepatic Biliary System by Three-Dimensional Reconstruction

Masyuk

Ritman

LaRusso

2001

The American Journal of Pathology

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“…In ANIT toxicity, glycosuria is caused by increased biliary levels of glucose. This is the result of a reduction in the capacity of the biliary epithelium to reabsorb glucose because of epithelial cell damage/necrosis and obstruction of bile duct lumen (Kossor et al 1998). The observation that blood plasma glucose was increased and hepatic glucose and glycogen content decreased in rats dosed with any of the three toxicants suggests that either this action is caused by NA, the common intermediate to all three experiments, or that all three compounds similarly target the bile duct lumen.…”

Section: Discussionmentioning

confidence: 96%

“…1-Naphthylisothiocyanate (ANIT) is a model hepatotoxin, previously employed in the study of mechanisms of intrahepatic cholestasis, with its action being both highly reproducible between studies and dose-dependent (Goldfarb et al 1962;Kossor et al 1998;Azmi et al 2002). The pathophysiological effects of ANIT-induced liver toxicity include bile duct epithelial cell necrosis and hepatic parenchymal cell injury, followed by bile duct proliferation, cessation of bile flow and consequently hyperbilirubinaemia (Goldfarb et al 1962).…”

Section: Introductionmentioning

confidence: 98%

Chemometric analysis of biofluids following toxicant induced hepatotoxicity: A metabonomic approach to distinguish the effects of 1-naphthylisothiocyanate from its products

Azmi

Griffin

Shore³

et al. 2005

Xenobiotica

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Metabonomics using high-resolution 1H-NMR spectroscopy of biofluids and pattern recognition is highly successful at distinguishing both organ- and sub-organ-specific toxicity. In the current study, this technique was investigated to distinguish the different biological effects caused by 1-naphthylisothiocyanate (ANIT)-induced hepatotoxicity in the rat from that induced by exposure to 1-naphthylisocyanate (NI) and 1-naphthylamine (NA), two products of the metabolism of ANIT. While all three toxicants produced perturbations in similar urinary metabolites, principal components analysis of the temporal progression identified that the rapid initial glycosuria associated with ANIT toxicity was also present with NI but not NA dosing. However, longer-term perturbations in the urinary excretion of succinate, lactate and acetate were common to all three toxicants. The metabolic effects of the three compounds were also followed in blood plasma and liver tissue. Of the three toxicants, the most marked perturbations were induced by ANIT exposure, then NI, thereby indicating the effects of ANIT, NI and NA toxicity were distinct, with ANIT being the most, and NA the least, toxic of the three compounds. This indicates that metabonomics may be useful for following severity and mechanisms of toxicity in a series of related compounds during drug development.

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“…Treatment of rats with ANIT (75–150 mg/kg) has resulted in biliary epithelial cell (BEC) necrosis followed by bile duct obstruction, cholestasis, and finally Type I BEC hyperplasia (Kossor et al, 1995). More recent publications have indicated that ANIT-induced hyperplasia may not be due to bile duct obstruction (Kossor et al, 1998). ANIT-induced toxicity to BEC and hepatocytes (HPC) has been shown to involve glutathione (Carpenter-Deyo et al, 1991; Jean and Roth, 1995), the accumulation of ANIT in the bile (Jean et al, 1995), and the release of toxic elements by neutrophils (Dahm et al, 1991a, 1991b; Hill and Roth, 1998; Jean et al, 1998; Hill et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Characterization of ANIT-Induced Toxicity using Precision-Cut Rat and Dog Liver Slices Cultured in a Dynamic Organ Roller System

Amin

Sato

et al. 2006

Toxicol Pathol

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This article describes the toxicity of α-naphthylisothiocyanate (ANIT), a compound known to induce dose-dependent hepatobiliary toxicity in vivo, using the slice model. Liver slices (200 µm thick) from male Sprague-Dawley rats and male beagle dogs were cultured for 7 days while exposed to a range of ANIT concentrations (1-100 µM for rat and 4-320 µM for dog). Tissues (and medium for dog) were evaluated using a panel of clinically relevant biomarkers for liver and histological endpoints to assess viability and proliferation. ANIT increased slice levels of enzyme biomarkers corresponding to biliary markers. At high concentrations (80-100 µM for rat, 320 µM for dog) a diminution of tissue enzyme levels was observed, corresponding to severe hepatobiliary injury. By days 5 and 7, biochemical markers in the medium of dog slices indicated an elevation of hepatocellular and biliary markers. Histologically for both species, minimal hepatocellular injury was noted, but proliferation of biliary epithelial cells (BEC) was observed using 5-bromo-2-deoxyuridine (BrdU) immunostaining. In rat slices, ANIT increased the expression of inducible nitrous oxide synthase (iNOS) within 12 hrs of exposure. In summary, additional experimentation using slice culture may further demonstrate its value in screening compounds that cause hepatobiliary toxicity.

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Bile Duct Obstruction Is not a Prerequisite for Type I Biliary Epithelial Cell Hyperplasia

Cited by 13 publications

References 26 publications

Quantitative Assessment of the Rat Intrahepatic Biliary System by Three-Dimensional Reconstruction

Quantitative Assessment of the Rat Intrahepatic Biliary System by Three-Dimensional Reconstruction

Chemometric analysis of biofluids following toxicant induced hepatotoxicity: A metabonomic approach to distinguish the effects of 1-naphthylisothiocyanate from its products

Characterization of ANIT-Induced Toxicity using Precision-Cut Rat and Dog Liver Slices Cultured in a Dynamic Organ Roller System

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