101. Validation of precision-cut liver slices to study drug-induced cholestasis: a transcriptomics approach
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Geny M. M. Groothuis, Peter Olinga, Suresh Vatakuti, Jeroen L. A. Pennings, Groningen Research Institute of Pharmacy, Nanomedicine and Drug Targeting (GRIP), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Pharmaceutical Technology and Biopharmacy, Nanomedicine & Drug Targeting, and Groningen Institute for Organ Transplantation (GIOT)
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Chlorpromazine ,medicine.drug_class ,Health, Toxicology and Mutagenesis ,Biology ,Ethinyl Estradiol ,Toxicology ,Organ Toxicity and Mechanisms ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,Cholestasis ,1-Naphthylisothiocyanate ,Methyltestosterone ,Internal medicine ,medicine ,Humans ,Transcriptomics ,Aged ,Precision-cut liver slices ,Dose-Response Relationship, Drug ,Bile acid ,Cholesterol ,Gene Expression Profiling ,Hepatotoxicity ,General Medicine ,Middle Aged ,medicine.disease ,Protein ubiquitination ,030104 developmental biology ,Endocrinology ,Liver ,chemistry ,Toxicity ,Cyclosporine ,Unfolded protein response ,Female ,Farnesoid X receptor ,Transcriptome ,Signal Transduction - Abstract
Hepatotoxicity is one of the major reasons for withdrawal of drugs from the market. Therefore, there is a need to screen new drugs for hepatotoxicity in humans at an earlier stage. The aim of this study was to validate human precision-cut liver slices (PCLS) as an ex vivo model to predict drug-induced cholestasis and identify the possible mechanisms of cholestasis-induced toxicity using gene expression profiles. Five hepatotoxicants, which are known to induce cholestasis (alpha-naphthyl isothiocyanate, chlorpromazine, cyclosporine, ethinyl estradiol and methyl testosterone) were used at concentrations inducing low (
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