PUBLICATION
Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?
- Authors
- Mesens, N., Crawford, 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.
- ID
- ZDB-PUB-150211-21
- Date
- 2015
- Source
- Journal of applied toxicology : JAT 35(9): 1017-29 (Journal)
- Registered Authors
- Crawford, Alexander
- Keywords
- DILI, hepatotoxicity, lfabp10a, screening assay, zebrafish larvae
- MeSH Terms
-
- Animal Use Alternatives/methods*
- Animals
- Chemical and Drug Induced Liver Injury/etiology*
- Chemical and Drug Induced Liver Injury/genetics
- Chemical and Drug Induced Liver Injury/metabolism
- Dose-Response Relationship, Drug
- Fatty Acid-Binding Proteins/genetics
- Gene Expression/drug effects
- In Situ Hybridization
- Larva/drug effects
- Larva/genetics
- Liver/drug effects*
- Liver/metabolism
- Logistic Models
- Pharmaceutical Preparations/administration & dosage*
- Toxicity Tests/methods*
- Zebrafish/genetics
- Zebrafish/physiology*
- Zebrafish Proteins/genetics
- PubMed
- 25663337 Full text @ J. Appl. Toxicol.
- CTD
- 25663337
Citation
Mesens, N., Crawford, 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. (2015) Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?. Journal of applied toxicology : JAT. 35(9):1017-29.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping