Acute toxicity of CCl4 but not of paracetamol induces a transcriptomic signature of fibrosis in precision-cut liver slices

被引：24
作者：
Vatakuti, Suresh [1 ]
Schoonen, Willem G. E. J.
Elferink, Marieke L. G. [1 ]
Groothuis, Geny M. M. [1 ]
Olinga, Peter [2 ]
机构：
[1] Univ Groningen, Groningen Res Inst Pharm, Dept Pharm, Div Pharmacokinet Toxicol & Targeting, NL-9713 AV Groningen, Netherlands
[2] Univ Groningen, Groningen Res Inst Pharm, Dept Pharm, Div Pharmaceut Technol & Biopharm, NL-9713 AV Groningen, Netherlands
来源：
TOXICOLOGY IN VITRO | 2015年 / 29卷 / 05期
关键词：
Prediction of fibrosis; Precision cut liver slices; Paracetamol; CCl4; STELLATE CELL ACTIVATION; HEPATIC-FIBROSIS; IN-VIVO; GENE; PROLIFERATION; MODULATION; MODEL;
D O I：
10.1016/j.tiv.2015.03.015
中图分类号：
R99 [毒物学（毒理学）];
学科分类号：
100405 ;
摘要：
In rat in vivo, both paracetamol (APAP) and carbon tetrachloride (CCl4) induce liver necrosis, but longterm 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 and CCl4 was 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, mitogenactivated 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. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码：1012 / 1020
页数：9
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