Title
Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?
Author
Mesens, N.
Crawfordb, A.D.
Menke, A.
Hung, P.D.
van Goethem, F.
Nuyts, R.
Hansen, E.
Wolterbeek, A.
van Gompel, J.
de Witte, P.
Esguerra, C.V.
Publication year
2015
Abstract
Drug-induced liver injury (DILI) is poorly predicted by single-cell-based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for DILI; however, the possible occurrence of other organ toxicities and the immature larval stage of the zebrafish might complicate accurate and fast analysis. We investigated whether expression analysis of liver-specific fatty acid binding protein 10a (lfabp10a) was an appropriate endpoint for assessing hepatotoxic effects in zebrafish larvae. It was found that expression analysis of lfabp10a was a valid marker, as after treatment with hepatotoxicants, dose-response curves could be obtained and statistically significant abnormal lfabp10 expression levels correlated with hepatocellular histopathological changes in the liver. However, toxicity in other vital organs such as the heart could impact liver outgrowth and thus had to be assessed concurrently. Whether zebrafish larvae were suitable for assessing human relevant drug-induced hepatotoxicity was assessed with hepatotoxicants and non-hepatotoxicants that have been marketed for human use and classified according to their mechanism of toxicity. The zebrafish larva showed promising predictivity towards a number of mechanisms and was capable of distinguishing between hepatotoxic and non-hepatotoxic chemical analogues, thus implying its applicability as a potential screening model for DILI. © 2015 John Wiley & Sons, Ltd.
Subject
Life
RAPID - Risk Analysis for Products in Development
ELSS - Earth, Life and Social Sciences
Food and Nutrition
Nutrition
Healthy Living
Zebrafish larvae
Screening assay
Lfabp10a
Hepatotoxicity
DILI
Alpidem
Amiodarone
Bosentan
Buspirone
Diclofenac
Fatty acid binding protein
Fatty acid binding protein 10a
Glycogen
Ketorolac
Nefazodone
Paracetamol
Reactive oxygen metabolite
Rosiglitazone
Tacrine
Tamoxifen
Tetracycline
Troglitazone
Unclassified drug
Zolpidem
Adult
Animal tissue
Cell vacuole
Cholestasis
Circulation
Concentration response
Controlled study
Drug safety
Female
Glycogen analysis
Heart rate
Histology
Histopathology
In situ hybridization
Larval stage
Liver cell
Liver level
Liver size
Liver toxicity
Male
Mitochondrial membrane
Mitochondrial toxicity
Molecular cloning
Nonhuman
Protein expression
Steatosis
Toxicity testing
Zebra fish
Danio rerio
To reference this document use:
http://resolver.tudelft.nl/uuid:dedc8759-4f01-4957-aa6f-5e46e4e93351
DOI
https://doi.org/10.1002/jat.3091
TNO identifier
525826
Source
Journal of Applied Toxicology, 35 (9), 1017-1029
Document type
article