title: Acute toxicity of CCl4 but not of paracetamol induces a transcriptomic signature of fibrosis in precision-cut liver slices.
abstract: In rat in vivo, both paracetamol (APAP) and carbon tetrachloride (CCl4) induce liver necrosis, but long-term treatment with CCl4, in contrast to paracetamol, causes liver fibrosis. The aim of this study was to perform transcriptomic analysis to compare the early changes in mRNA expression profiles induced by APAP and CCl4 in the rat precision-cut liver slice model (PCLS) and to identify early markers that could predict fibrosis-inducing potential. Microarray data of rat PCLS exposed to APAP andCCl4was generated using a toxic dose based on decrease in ATP levels. Toxicity pathway analysis using a custom made fibrosis-related gene list showed fibrosis as one of the predominant toxic endpoints in CCl4-treated, but not in APAP-treated PCLS. Moreover, genes which have a role in fibrosis such as alpha-B crystallin, jun proto-oncogene, mitogen-activated protein kinase 6, serpin peptidase inhibitor and also the transcription factor Kruppel-like-factor-6 were up-regulated by CCl4, but not by APAP. Predicted activation or inhibition of several upstream regulators due to CCl4 is in accordance with their role in fibrosis. In conclusion, transcriptomic analysis of PCLS successfully identified the fibrotic potential of CCl4 as opposed to APAP. The application of PCLS as an ex vivo model to identify early biomarkers to predict the fibrogenic potential of toxic compounds should be further explored.
authors: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors: Suresh
authors: S
authors: Vatakuti
authors: Toxicology Consultant, Oss, The Netherlands.
authors: Willem G E J
authors: WG
authors: Schoonen
authors: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors: Marieke L G
authors: ML
authors: Elferink
authors: Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors: Geny M M
authors: GM
authors: Groothuis
authors: Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands. Electronic address: p.olinga@rug.nl.
authors: Peter
authors: P
authors: Olinga
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: D012333:RNA, Messenger; D000082:Acetaminophen; D002251:Carbon Tetrachloride
keywords: CCl(4); Paracetamol; Precision cut liver slices; Prediction of fibrosis