ArticleBMC medical genomics2013
Treatment of mouse liver slices with cholestatic hepatotoxicants results in down-regulation of Fxr and its target genes.
Article in BMC medical genomics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 31 citations in OpenAlex.
- Comparative Analysis of Species-Specific Hepatocyte Function and Drug Effects in a Liver Microphysiological System PhysioMimix LC12 and 96-Well Plates.ACS pharmacology & translational science · 2025Article
- Cell-based approaches for the mechanistic understanding of drug-induced cholestatic liver injury.Archives of toxicology · 2025Review
- Chenodeoxycholic acid alleviated the cyclosporine-induced nephrotoxicity by decreasing oxidative stress and suppressing renin-angiotensin system through AT2R and ACE2 mRNA upregulation in rats.Journal of molecular histology · 2024Article
- The regulatory effects of second-generation antipsychotics on lipid metabolism: Potential mechanisms mediated by the gut microbiota and therapeutic implications.Frontiers in pharmacology · 2023Review
- Mouse precision-cut liver slices as an ex vivo model to study drug-induced cholestasis.Archives of toxicology · 2022Article
- Best Practices and Progress in Precision-Cut Liver Slice Cultures.International journal of molecular sciences · 2021Review
- Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures.Archives of toxicology · 2018Article
- Rat precision-cut liver slices predict drug-induced cholestatic injury.Archives of toxicology · 2017Article
- Validation of precision-cut liver slices to study drug-induced cholestasis: a transcriptomics approach.Archives of toxicology · 2017Article
- Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in Mice.Cellular and molecular gastroenterology and hepatology · 2017Article
- Role of endoplasmic reticulum stress in drug-induced toxicity.Pharmacology research & perspectives · 2016Review
- Article
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5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundUnexpected cholestasis substantially contributes to drug failure in clinical trials. Current models used for safety assessment in drug development do not accurately predict cholestasis in humans. Therefore, it is of relevance to develop new screening models that allow identifying drugs with cholestatic properties.
methodsWe employed mouse precision cut liver slices (PCLS), which were incubated 24 h with two model cholestatic compounds: cyclosporin A (CsA) and chlorpromazine (CPZ). Subsequently, transcriptome analysis using DNA microarrays and q-PCR were performed to identify relevant biological processes and biomarkers. Additionally, histology was carried out and levels of triglycerides (TG) and bile acids (BA) were measured. To verify the ex vivo mouse data, these were compared with publically available human data relevant for cholestasis.
resultsWhole genome gene expression analysis showed that CsA up-regulated pathways related to NF-κB, ER stress and inflammation. Both CsA and CPZ down-regulated processes related to extracellular matrix (ECM) remodelling, BA homeostasis, Fxr signalling, and energy metabolism. The differential expression of a number of characteristic genes (e.g. Abcg5, Abcg8, Klf15, and Baat) could be confirmed by q-PCR. Histology revealed that CsA but not CPZ induced "ballooning" of hepatocytes. No effects on TG and BA levels were observed after incubation of PCLS with CsA and CPZ. A substantial number of processes altered in CsA- and CPZ-treated mouse PCLS ex vivo was also found to be affected in liver biopsies of cholestatic patients.
conclusionThe present study demonstrated that mouse PCLS can be used as a tool to identify mechanisms of action of cholestatic model compounds. The induction of general stress responses and down-regulated Fxr signalling could play a role in the development of drug induced cholestasis. Importantly, comparative data analysis showed that the ex vivo mouse findings are also relevant for human pathology. Moreover, this work provides a set of genes that are potentially useful to assess drugs for cholestatic properties.
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