Biliary Epithelial Cell Proliferation Following α-Naphthylisothiocyanate (ANIT) Treatment: Relationship to Bile Duct Obstruction

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

doi:10.1093/toxsci/26.1.51

Cited by 6 publications

(7 citation statements)

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“…Administration of high doses of ANIT or feeding a diet containing 0.1% ANIT to mice induces BDEC proliferation, which reflects a compensatory response to the damaging effects of ANIT (1,35,36). We found that TF staining was associated with areas of BDEC proliferation after ANIT treatment.…”

Section: Discussionmentioning

confidence: 67%

Tissue factor-dependent coagulation contributes to α-naphthylisothiocyanate-induced cholestatic liver injury in mice

Luyendyk¹,

Cantor²,

Kirchhofer³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Separation of concentrated bile acids from hepatic parenchymal cells is a key function of the bile duct epithelial cells (BDECs) that form intrahepatic bile ducts. Using coimmunostaining, we found that tissue factor (TF), the principal activator of coagulation, colocalized with cytokeratin 19, a marker of BDECs in the adult mouse liver. BDEC injury induced by xenobiotics such as alpha-naphthylisothiocyanate (ANIT) causes cholestasis, inflammation, and hepatocellular injury. We tested the hypothesis that acute ANIT-induced cholestatic hepatitis is associated with TF-dependent activation of coagulation and determined the role of TF in ANIT hepatotoxicity. Treatment of mice with ANIT (60 mg/kg) caused multifocal hepatic necrosis and significantly increased serum biomarkers of cholestasis and hepatic parenchymal cell injury. ANIT treatment also significantly increased liver TF expression and activity. ANIT-induced activation of the coagulation cascade was shown by increased plasma thrombin-antithrombin levels and significant deposition of fibrin within the necrotic foci. ANIT-induced coagulation and liver injury were reduced in low-TF mice, which express 1% of normal TF levels. The results indicate that ANIT-induced liver injury is accompanied by TF-dependent activation of the coagulation cascade and that TF contributes to the progression of injury during acute cholestatic hepatitis.

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Section: Discussionmentioning

confidence: 67%

Tissue factor-dependent coagulation contributes to α-naphthylisothiocyanate-induced cholestatic liver injury in mice

Luyendyk¹,

Cantor²,

Kirchhofer³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In this model of chemically induced intrahepatic cholestasis, ANIT damages the cholangiocytes lining the bile duct after glutathione conjugation in the liver and transport across the canalicular membrane by MRP2. 24,29 As a consequence, cessation of bile flow is observed within 24 hours. 30 Third, we crossed our iVP16FXR mouse with the Mdr2 Ϫ/Ϫ mouse, a model of genetically induced intrahepatic cholestasis.…”

Section: Discussionmentioning

confidence: 99%

“…To this end, we treated iVP16 and iVP16FXR mice with ␣-naphthylisothiocyanate (ANIT), a compound that damages biliary epithelial cells and induces intrahepatic cholestasis. 24,25 As a control, we treated mice with vehicle alone (olive oil). In the ANIT-treated group, more severe liver damage in iVP16 mice than in iVP16FXR mice was indicated by the yellowish color saturation of serum (Figure 4A).…”

Section: Selective Activation Of Intestinal Fxr Protects Against Chemmentioning

confidence: 99%

Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis

et al. 2012

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“…However, ANIT causes hepatic damage through a different mechanism from APAP. ANIT induces cholestasis as a result of the ABC transporter multidrug resistance-related protein 2 excreting a toxic GSHconjugated ANIT metabolite across the canalicular membrane where it subsequently damages the cholangiocytes lining the bile ducts (43,44). Interestingly, an earlier study demonstrated that pretreatment of rats with the FXR agonist GW4064 provided partial protection from ANIT-induced hepatic necrosis and inflammatory cell infiltration (42).…”

mentioning

confidence: 99%

Activation of the Farnesoid X Receptor Provides Protection against Acetaminophen-Induced Hepatic Toxicity

Lee¹,

Vallim

Chong

et al. 2010

Molecular Endocrinology

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The nuclear receptor, farnesoid X receptor (FXR, NR1H4), is known to regulate cholesterol, bile acid, lipoprotein, and glucose metabolism. In the current study, we provide evidence to support a role for FXR in hepatoprotection from acetaminophen (APAP)-induced toxicity. Pharmacological activation of FXR induces the expression of several genes involved in phase II and phase III xenobiotic metabolism in wild-type, but not Fxr(-/-) mice. We used chromatin immunoprecipitation-based genome-wide response element analyses coupled with luciferase reporter assays to identify functional FXR response elements within promoters, introns, or intragenic regions of these genes. Consistent with the observed transcriptional changes, FXR gene dosage is positively correlated with the degree of protection from APAP-induced hepatotoxicity in vivo. Further, we demonstrate that pretreatment of wild-type mice with an FXR-specific agonist provides significant protection from APAP-induced hepatotoxicity. Based on these findings, we propose that FXR plays a role in hepatic xenobiotic metabolism and, when activated, provides hepatoprotection against toxins such as APAP.

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Biliary Epithelial Cell Proliferation Following α-Naphthylisothiocyanate (ANIT) Treatment: Relationship to Bile Duct Obstruction

Cited by 6 publications

References 0 publications

Tissue factor-dependent coagulation contributes to α-naphthylisothiocyanate-induced cholestatic liver injury in mice

Tissue factor-dependent coagulation contributes to α-naphthylisothiocyanate-induced cholestatic liver injury in mice

Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis

Activation of the Farnesoid X Receptor Provides Protection against Acetaminophen-Induced Hepatic Toxicity

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