title: Rat precision-cut liver slices predict drug-induced cholestatic injury.
abstract: 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 μM 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.
authors.affiliation: Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Viktoriia
authors.initials: V
authors.lastname: Starokozhko
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Greupink
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: van de Broek
authors.affiliation: Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Nashwa
authors.initials: N
authors.lastname: Soliman
authors.affiliation: Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Samiksha
authors.initials: S
authors.lastname: Ghimire
authors.affiliation: Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Inge A M
authors.initials: IAM
authors.lastname: de Graaf
authors.affiliation: Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands. g.m.m.groothuis@rug.nl.
authors.forename: Geny M M
authors.initials: GMM
authors.lastname: Groothuis
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11 / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002779:Cholestasis / Q000139:chemically induced; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009924:Organ Culture Techniques / Q000379:methods*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics; D017208:Rats, Wistar; D027981:Symporters / Q000235:genetics; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; C490548:Abcb11 protein, rat; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter
keywords: Bile acids; Drug-induced cholestasis; Drug-induced liver injury; Precision-cut liver slices