title: Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?
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.
authors: Discovery Support and Investigative Toxicology group EU, Preclinical Development and Safety, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors: Natalie
authors: N
authors: Mesens
authors: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven Campus Gasthuisberg, O&N 2, 08.4226 Herestraat 49, PB 824, 3000, Leuven, Belgium.
authors: Alexander D
authors: AD
authors: Crawford
authors: TNO, Utrechtseweg 48, 3704HE, Zeist, The Netherlands.
authors: Aswin
authors: A
authors: Menke
authors: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven Campus Gasthuisberg, O&N 2, 08.4226 Herestraat 49, PB 824, 3000, Leuven, Belgium.
authors: Pham Duc
authors: PD
authors: Hung
authors: Discovery Support and Investigative Toxicology group EU, Preclinical Development and Safety, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors: Freddy
authors: F
authors: Van Goethem
authors: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven Campus Gasthuisberg, O&N 2, 08.4226 Herestraat 49, PB 824, 3000, Leuven, Belgium.
authors: Rik
authors: R
authors: Nuyts
authors: Discovery Support and Investigative Toxicology group EU, Preclinical Development and Safety, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors: Erik
authors: E
authors: Hansen
authors: TNO, Utrechtseweg 48, 3704HE, Zeist, The Netherlands.
authors: Andre
authors: A
authors: Wolterbeek
authors: Discovery Support and Investigative Toxicology group EU, Preclinical Development and Safety, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors: Jacky
authors: J
authors: Van Gompel
authors: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven Campus Gasthuisberg, O&N 2, 08.4226 Herestraat 49, PB 824, 3000, Leuven, Belgium.
authors: Peter
authors: P
authors: De Witte
authors: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven Campus Gasthuisberg, O&N 2, 08.4226 Herestraat 49, PB 824, 3000, Leuven, Belgium.
authors: Camila V
authors: CV
authors: Esguerra
mesh_terms: D023401:Animal Use Alternatives / Q000379:methods*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D017403:In Situ Hybridization; D007814:Larva / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D016015:Logistic Models; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D018675:Toxicity Tests / Q000379:methods*; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D050556:Fatty Acid-Binding Proteins; D004364:Pharmaceutical Preparations; D029961:Zebrafish Proteins; C513422:fatty acid-binding protein 10, zebrafish
keywords: DILI; hepatotoxicity; lfabp10a; screening assay; zebrafish larvae