Neutrophil- and Glutathione-Mediated Hepatotoxicity of<i>α</i>-Naphthylisothiocyanate

Roth, Robert A.; Dahm, Lawrence J.

doi:10.3109/03602539709037578

Cited by 56 publications

(64 citation statements)

References 27 publications

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“…This may represent one mechanism for the reported hepatotoxicity of 1-NITC. 37 Recently, Dietrich and coworkers found that 1-NITC-SG was actively transported by MRP2 in the canine kidney cell line MDCK II transfected by the human MRP2 gene. 38 Moreover, the authors of that study found the depletion of cellular GSH concentration was due to a cycling of 1-NITC/1-NITC-SG, similar to the proposed mechanism for BITC and PEITC.…”

Section: Discussionmentioning

confidence: 99%

“…13,35 Alternatively, 1-NITC is enzymatically hydrolyzed to form 1-NA via 1-NIC as the intermediate, 35 predominantly mediated by CYP1A1, 16 and the major metabolite found in the urine in rats is 1-NA. 13 It has been proposed that 1-NITC-SG can be formed in the liver, and would be actively exported by MRP2 from hepatic parenchymal cells to bile, 36,37 and that the dissociation of 1-NITC-SG in the bile could result in an elevation of GSH concentration and exposure of bile duct epithelial cells and periportal parenchymal cells to large and possibly toxic concentrations of 1-NITC. This may represent one mechanism for the reported hepatotoxicity of 1-NITC.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Benzyl‐, Phenethyl‐, and α‐naphthyl Isothiocyanates on P‐glycoprotein‐ and MRP1‐mediated Transport

Morris

2004

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Benzyl‐, Phenethyl‐, and α‐naphthyl Isothiocyanates on P‐glycoprotein‐ and MRP1‐mediated Transport

Morris

2004

Journal of Pharmaceutical Sciences

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“…In this intrahepatic rodent model of cholestasis, ANIT is conjugated to glutathione in the hepatocyte and then transported across the canalicular membrane by MRP2, where it damages the cholangiocytes lining the bile ducts (25,49). Cessation of bile flow is seen within 24 hours (50). The BDL rat model is a severe model of extrahepatic obstructive cholestasis.…”

Section: Figurementioning

confidence: 99%

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis

Liu¹,

Binz²,

Numerick³

et al. 2003

J. Clin. Invest.

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Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and α-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.This article was publised online in advance of the print addition. The date of publication is available from the JCI website, http://www.jci.org.

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“…The mechanisms of ANIT-induced liver injury have been proposed but they have not been proven [Roth and Dahm, 1997]. In this context, Calcamuggi et al [1992] suggested that endotoxemia may play a pathogenic role in ANIT-induced liver injury in rats and other studies demonstrated that glutathione plays an important role in ANIT hepatotoxicity [Jean and Roth, 1995].…”

mentioning

confidence: 99%

Characterization of the protective effects of melatonin and related indoles against ?-naphthylisothiocyanate-induced liver injury in rats

et al. 2001

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The protective effect of melatonin, 6-hydroxymelatonin and N-acetylserotonin against alpha-naphthylisothiocyanate (ANIT)-induced liver injury was investigated and compared in rats injected once with the hepatotoxicant (75 mg/kg body weight). In rats injected with ANIT alone, liver injury with cholestasis developed within 24 h, as indicated by both serum levels of alanine aminotransferase (SGPT) and aspartic acid aminotransferase (SGOT) activities and serum total bilirubin concentration. The administration of melatonin or 6-hydroxymelatonin (10 mg/kg body weight) to ANIT-injected rats reduced significantly the serum levels of both SGPT and SGOT and the serum total bilirubin concentration. For all hepatic biochemical markers, melatonin was more effective that 6-hydroxymelatonin. By comparison, the administration of N-acetylserotonin (10 mg/kg body weight) to ANIT-injected rats did not reduce the serum levels of either hepatic enzymes or the serum total bilirubin concentration. In ANIT-injected rats, hepatic lipid peroxidation (LPO) was significantly higher than in control animals and this increase was significantly reduced by either melatonin, 6-hydroxymelatonin or N-acetylserotonin. Furthermore, ANIT treatment caused a significant reduction in liver microsomal membrane fluidity and this reduction was completely reversed by the three indoles. The liver from ANIT-injected rats showed several histopathological alterations; above all there was an acute infiltration of polymorphonuclear neutrophils and an increase in the number of apparent apoptotic hepatocytes. The concurrent administration of melatonin reduced the severity of all morphological alterations, specially the neutrophil infiltration and the number of presumed apoptotic cells. On the contrary, the administration of 6-hydroxymelatonin or N-acetylserotonin did not provide any protective effect in terms of the histopathological alterations. These results indicate that melatonin protects against ANIT-induced liver injury with cholestasis in rats, and suggests that this protective effect is likely due to its antioxidant properties and above all to its capacity to inhibit liver neutrophil infiltration, a critical factor in the pathogenesis of ANIT-induced liver injury. 6-hydroxymelatonin, although able to provide partial protection against the ANIT-induced hepatic injury, probably through its antioxidant properties by mechanisms that are unclear, was unable to reduce neutrophil infiltration. Finally, N-acetylserotonin in the experimental conditions of this study, only exhibited some antioxidant protection but had no protective effect against ANIT-induced hepatic damage.

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Neutrophil- and Glutathione-Mediated Hepatotoxicity ofα-Naphthylisothiocyanate

Cited by 56 publications

References 27 publications

Effects of Benzyl‐, Phenethyl‐, and α‐naphthyl Isothiocyanates on P‐glycoprotein‐ and MRP1‐mediated Transport

Effects of Benzyl‐, Phenethyl‐, and α‐naphthyl Isothiocyanates on P‐glycoprotein‐ and MRP1‐mediated Transport

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis

Characterization of the protective effects of melatonin and related indoles against ?-naphthylisothiocyanate-induced liver injury in rats

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