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Int. J. Mol. Sci. 2017, 18(1), 217; doi:10.3390/ijms18010217

In Vitro Biotransformation of Two Human CYP3A Probe Substrates and Their Inhibition during Early Zebrafish Development

1
Applied Veterinary Morphology, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Antwerp, Belgium
2
Wilson Tox Lab, Department of Biology, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Juliette Legler
Received: 15 December 2016 / Revised: 11 January 2017 / Accepted: 17 January 2017 / Published: 22 January 2017
(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)
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Abstract

At present, the zebrafish embryo is increasingly used as an alternative animal model to screen for developmental toxicity after exposure to xenobiotics. Since zebrafish embryos depend on their own drug-metabolizing capacity, knowledge of their intrinsic biotransformation is pivotal in order to correctly interpret the outcome of teratogenicity assays. Therefore, the aim of this in vitro study was to assess the activity of cytochrome P450 (CYP)—a group of drug-metabolizing enzymes—in microsomes from whole zebrafish embryos (ZEM) of 5, 24, 48, 72, 96 and 120 h post-fertilization (hpf) by means of a mammalian CYP substrate, i.e., benzyloxy-methyl-resorufin (BOMR). The same CYP activity assays were performed in adult zebrafish liver microsomes (ZLM) to serve as a reference for the embryos. In addition, activity assays with the human CYP3A4-specific Luciferin isopropyl acetal (Luciferin-IPA) as well as inhibition studies with ketoconazole and CYP3cide were carried out to identify CYP activity in ZLM. In the present study, biotransformation of BOMR was detected at 72 and 96 hpf; however, metabolite formation was low compared with ZLM. Furthermore, Luciferin-IPA was not metabolized by the zebrafish. In conclusion, the capacity of intrinsic biotransformation in zebrafish embryos appears to be lacking during a major part of organogenesis. View Full-Text
Keywords: zebrafish; embryo; development; cytochrome P450; activity; in vitro; and biotransformation zebrafish; embryo; development; cytochrome P450; activity; in vitro; and biotransformation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Verbueken, E.; Alsop, D.; Saad, M.A.; Pype, C.; Van Peer, E.M.; Casteleyn, C.R.; Van Ginneken, C.J.; Wilson, J.; Van Cruchten, S.J. In Vitro Biotransformation of Two Human CYP3A Probe Substrates and Their Inhibition during Early Zebrafish Development. Int. J. Mol. Sci. 2017, 18, 217.

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