ArticleToxicological sciences : an official journal of the Society of Toxicology2009
ANIT-induced intrahepatic cholestasis alters hepatobiliary transporter expression via Nrf2-dependent and independent signaling.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 125 citations in OpenAlex.
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- Investigation of the usefulness of liver-specific deconvolution method by establishing a liver benchmark dataset.NAR genomics and bioinformatics · 2024Article
- Papaverine attenuates the progression of alpha naphthylisothiocyanate induce cholestasis in rats.Current research in pharmacology and drug discovery · 2024Article
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- Ginsenosides Restore Lipid and Redox Homeostasis in Mice with Intrahepatic Cholestasis through SIRT1/AMPK Pathways.Nutrients · 2022Article
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- Oltipraz ameliorates the progression of steatohepatitis in Nrf2-null mice fed a high-fat diet.Journal of clinical biochemistry and nutrition · 2022Article
- Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model.PloS one · 2022Article
- Involvement of endoplasmic reticulum stress in rifampicin-induced liver injury.Frontiers in pharmacology · 2022Review
- Glycyrrhetinic Acid Protects α-Naphthylisothiocyanate- Induced Cholestasis Through Regulating Transporters, Inflammation and Apoptosis.Frontiers in pharmacology · 2021Article
- BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination.JCI insight · 2020Article
- Intestinal Microbiome-Macrophage Crosstalk Contributes to Cholestatic Liver Disease by Promoting Intestinal Permeability in Mice.Hepatology (Baltimore, Md.) · 2020Article
- Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects.Antioxidants (Basel, Switzerland) · 2020Review
- Effects of ablation and activation of Nrf2 on bile acid homeostasis in male mice.Toxicology and applied pharmacology · 2020Article
- LCAT protects against Lipoprotein-X formation in a murine model of drug-induced intrahepatic cholestasis.Pharmacology research & perspectives · 2020Article
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4 authors at 1 institution in 1 country.
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Abstract
Alpha-naphthylisothiocyanate (ANIT) causes intrahepatic cholestasis by injuring biliary epithelial cells. Adaptive regulation of hepatobiliary transporter expression has been proposed to reduce liver injury during cholestasis. Recently, the oxidative stress transcription factor Nrf2 (nf-e2-related factor 2) was shown to regulate expression of hepatobiliary transporters. The purpose of this study was to determine whether ANIT-induced hepatotoxicity and regulation of hepatobiliary transporters are altered in the absence of Nrf2. For this purpose, wild-type and Nrf2-null mice were administered ANIT (75 mg/kg po). Surprisingly, ANIT-induced hepatotoxicity was similar in both genotypes at 48 h. Accumulation of bile acids in serum and liver was lower in Nrf2-null mice compared with wild-types treated with ANIT. Transporter mRNA profiles differed between wild-type and Nrf2-null mice after ANIT. Bsep (bile salt export pump), Mdr2 (multidrug resistance gene), and Mrp3 (multidrug resistance-associated protein) efflux transporters were increased by ANIT in wild-type, but not in Nrf2-null mice. In contrast, mRNA expression of two hepatic uptake transporters, Ntcp (sodium-taurocholate cotransporting polypeptide) and Oatp1b2 (organic anion transporting peptide), were decreased in both genotypes after ANIT, with larger declines in Nrf2-null mice. mRNA expression of the transcriptional repressor of Ntcp, small heterodimeric partner (SHP), was increased in Nrf2-null mice after ANIT. Furthermore, hepatocyte nuclear factor 1alpha (HNF1alpha), which regulates Oatp1b2, was downregulated in ANIT-treated Nrf2-null mice. Preferential upregulation of SHP and downregulation of HNF1alpha and uptake transporters likely explains why Nrf2-null mice exhibited similar injury to wild-types after ANIT. A subsequent study revealed that treatment of mice with the Nrf2 activator oltipraz protects against ANIT-induced histological injury. Despite compensatory changes in Nrf2-null mice to limit ANIT toxicity, pharmacological activation of Nrf2 may represent a therapeutic option for intrahepatic cholestasis.
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