Characterization of Triptolide-Induced Hepatotoxicity by Imaging and Transcriptomics in a Novel Zebrafish Model.

Autor:	Vliegenthart ADB; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16?4TJ, UK., Wei C; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.; Center for Drug Evaluation, China Food and Drug Agency, Beijing 100083, China., Buckley C; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16?4TJ, UK., Berends C; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16?4TJ, UK., de Potter CMJ; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16?4TJ, UK., Schneemann S; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16?4TJ, UK., Del Pozo J; Easter Bush Pathology, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian EH25?9RG, UK., Tucker C; Biomedical Research Resources, The College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh EH16?4TJ, UK., Mullins JJ; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16?4TJ, UK., Webb DJ; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16?4TJ, UK., Dear JW; Edinburgh University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh EH16?4TJ, UK.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2017 Oct 01; Vol. 159 (2), pp. 380-391.
DOI:	10.1093/toxsci/kfx144
Abstrakt:	Triptolide is a vine extract used in traditional Chinese medicines and associated with hepatotoxicity. In vitro data suggest that inhibition of RNA synthesis may be the mechanism of toxicity. For studying drug-induced liver injury the zebrafish has experimental, practical and financial advantages compared with rodents. The aim of this study was to explore the mechanism of triptolide toxicity using zebrafish as the model system. The effect of triptolide exposure on zebrafish larvae was determined with regard to mortality, histology, expression of liver specific microRNA-122 and liver volume. Fluorescent microscopy was used to track toxicity in the Tg(-2.8lfabp:GFP)as3 zebrafish line. Informed by microscopy, RNA-sequencing was used to explore the mechanism of toxicity. Triptolide exposure resulted in dose-dependent mortality, a reduction in the number of copies of microRNA-122 per larva, hepatocyte vacuolation, disarray and oncotic necrosis, and a reduction in liver volume. These findings were consistent across replicate experiments. Time-lapse imaging indicated the onset of injury was 6 h after the start of exposure, at which point, RNA-sequencing revealed that 88% of genes were down-regulated. Immune response associated genes were up-regulated in the triptolide-treated larvae including nitric oxide synthase. Inhibition of nitric oxide synthase increased mortality. Triptolide induces hepatotoxicity in zebrafish larvae. This represents a new model of drug-induced liver injury that complements rodents. RNA sequencing, guided by time-lapse microscopy, revealed early down-regulation of genes consistent with previous invitro studies, and facilitated the discovery of mechanistic inflammatory pathways. (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.)
Databáze:	MEDLINE
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