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Int. J. Mol. Sci. 2019, 20(7), 1712; https://doi.org/10.3390/ijms20071712

Safety Assessment of Compounds after In Vitro Metabolic Conversion Using Zebrafish Eleuthero Embryos

1
Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 824, 3000 Leuven, Belgium
2
Pharmaceutical Analysis, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 923, 3000 Leuven, Belgium
3
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, O & N II Herestraat 49-box 921, 3000 Leuven, Belgium
4
L’Oréal Research & Innovation, 93600 Aulnay-sous-Bois, France
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: Department of Biochemistry, Hanoi University of Pharmacy, 100000 Hanoi, Vietnam.
§
Current address: Development Science, UCB Biopharma SPRL, 1420 Braine-l’Alleud, Belgium.
ǁ
Current address: Institutes of Integrative Medicine, Fudan University, 220 Handan Rd., Yangpu District, 200433 Shanghai, China.
Received: 22 March 2019 / Revised: 3 April 2019 / Accepted: 3 April 2019 / Published: 6 April 2019
(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)
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Abstract

Zebrafish-based platforms have recently emerged as a useful tool for toxicity testing as they combine the advantages of in vitro and in vivo methodologies. Nevertheless, the capacity to metabolically convert xenobiotics by zebrafish eleuthero embryos is supposedly low. To circumvent this concern, a comprehensive methodology was developed wherein test compounds (i.e., parathion, malathion and chloramphenicol) were first exposed in vitro to rat liver microsomes (RLM) for 1 h at 37 °C. After adding methanol, the mixture was ultrasonicated, placed for 2 h at −20 °C, centrifuged and the supernatant evaporated. The pellet was resuspended in water for the quantification of the metabolic conversion and the detection of the presence of metabolites using ultra high performance liquid chromatography-Ultraviolet-Mass (UHPLC-UV-MS). Next, three days post fertilization (dpf) zebrafish eleuthero embryos were exposed to the metabolic mix diluted in Danieau’s medium for 48 h at 28 °C, followed by a stereomicroscopic examination of the adverse effects induced, if any. The novelty of our method relies in the possibility to quantify the rate of the in vitro metabolism of the parent compound and to co-incubate three dpf larvae and the diluted metabolic mix for 48 h without inducing major toxic effects. The results for parathion show an improved predictivity of the toxic potential of the compound. View Full-Text
Keywords: drug discovery; toxicity; microsomes; metabolism; zebrafish eleuthero embryos drug discovery; toxicity; microsomes; metabolism; zebrafish eleuthero embryos
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Giusti, A.; Nguyen, X.-B.; Kislyuk, S.; Mignot, M.; Ranieri, C.; Nicolaï, J.; Oorts, M.; Wu, X.; Annaert, P.; De Croze, N.; Léonard, M.; Ny, A.; Cabooter, D.; de Witte, P. Safety Assessment of Compounds after In Vitro Metabolic Conversion Using Zebrafish Eleuthero Embryos. Int. J. Mol. Sci. 2019, 20, 1712.

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