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Rat precision-cut liver slices predict drug-induced cholestatic injury.
Starokozhko, Viktoriia; Greupink, Rick; van de Broek, Petra; Soliman, Nashwa; Ghimire, Samiksha; de Graaf, Inge A M; Groothuis, Geny M M.
Afiliação
  • Starokozhko V; Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
  • Greupink R; Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
  • van de Broek P; Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Soliman N; Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
  • Ghimire S; Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
  • de Graaf IAM; Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
  • Groothuis GMM; Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands. g.m.m.groothuis@rug.nl.
Arch Toxicol ; 91(10): 3403-3413, 2017 Oct.
Article em En | MEDLINE | ID: mdl-28391356
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Técnicas de Cultura de Órgãos / Testes de Toxicidade / Doença Hepática Induzida por Substâncias e Drogas / Fígado Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Técnicas de Cultura de Órgãos / Testes de Toxicidade / Doença Hepática Induzida por Substâncias e Drogas / Fígado Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article