Rat precision-cut liver slices predict drug-induced cholestatic injury
| Autor: | Geny M. M. Groothuis, Viktoriia Starokozhko, Rick Greupink, Samiksha Ghimire, Nashwa Soliman, Inge A. M. de Graaf, Petra van de Broek |
|---|---|
| Přispěvatelé: | Nanomedicine & Drug Targeting, Groningen Research Institute of Pharmacy, Biopharmaceuticals, Discovery, Design and Delivery (BDDD) |
| Jazyk: | angličtina |
| Předmět: |
Male
0301 basic medicine Drug-induced liver injury CYCLOSPORINE-A Health Toxicology and Mutagenesis Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] Pharmacology Toxicology Glibenclamide In Vitro Sysytems hemic and lymphatic diseases ATP Binding Cassette Transporter Subfamily B Member 11 media_common Liver injury Cholestasis Symporters Bile acid General Medicine 3. Good health medicine.anatomical_structure Liver Hepatocyte Toxicity INDUCED TOXICITY Chemical and Drug Induced Liver Injury FARNESOID-X-RECEPTOR medicine.drug Drug Drug-induced cholestasis medicine.drug_class media_common.quotation_subject INHIBITION Organic Anion Transporters Sodium-Dependent METABOLISM Biology Bile Acids and Salts 03 medical and health sciences Organ Culture Techniques Toxicity Tests medicine Animals HEPARG CELLS Rats Wistar Precision-cut liver slices medicine.disease TRANSPORTERS Bile acids SALT EXPORT PUMP Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] HUMAN HEPATOCYTES 030104 developmental biology Gene Expression Regulation Farnesoid X receptor BILE-ACID |
| Zdroj: | Archives of Toxicology, 91, 3403-3413 Archives of toxicology, 91(10), 3403-3413. SPRINGER HEIDELBERG Archives of Toxicology Archives of Toxicology, 91, 10, pp. 3403-3413 |
| ISSN: | 0340-5761 |
| DOI: | 10.1007/s00204-017-1960-7 |
| Popis: | Contains fulltext : 182162.pdf (Publisher’s version ) (Open Access) Drug-induced cholestasis (DIC) is one of the leading manifestations of drug-induced liver injury (DILI). As the underlying mechanisms for DIC are not fully known and specific and predictive biomarkers and pre-clinical models are lacking, the occurrence of DIC is often only reported when the drug has been approved for registration. Therefore, appropriate models that predict the cholestatic potential of drug candidates and/or provide insight into the mechanism of DIC are highly needed. We investigated the application of rat precision-cut liver slices (PCLS) to predict DIC, using several biomarkers of cholestasis: hepatocyte viability, intracellular accumulation of total as well as individual bile acids and changes in the expression of genes known to play a role in cholestasis. Rat PCLS exposed to the cholestatic drugs chlorpromazine, cyclosporine A and glibenclamide for 48 h in the presence of a 60 muM physiological bile acid (BA) mix reflected various changes associated with cholestasis, such as decrease in hepatocyte viability, accumulation and changes in the composition of BA and changes in the gene expression of Fxr, Bsep and Ntcp. The toxicity of the drugs was correlated with the accumulation of BA, and especially DCA and CDCA and their conjugates, but to a different extent for different drugs, indicating that BA toxicity is not the only cause for the toxicity of cholestatic drugs. Moreover, our study supports the use of several biomarkers to test drugs for DIC. In conclusion, our results indicate that PCLS may represent a physiological and valuable model to identify cholestatic drugs and provide insight into the mechanisms underlying DIC. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|