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Toxicol In Vitro. 2017 Aug;42:329-336. doi: 10.1016/j.tiv.2017.05.009. Epub 2017 May 12.

In vitro CYP-mediated drug metabolism in the zebrafish (embryo) using human reference compounds.

Author information

1
Applied Veterinary Morphology, Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
2
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
3
Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium; Flemish Institute for Technological Research (VITO), Business Unit Separation and Conversion Technology (SCT), Boeretang 200, 2400 Mol, Belgium.
4
Natural Products & Food Research and Analysis (NatuRA), University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
5
Applied Veterinary Morphology, Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. Electronic address: steven.vancruchten@uantwerpen.be.

Abstract

The increasing use of zebrafish embryos as an alternative model for toxicological and pharmacological studies necessitates a better understanding of xenobiotic biotransformation in this species. As cytochrome P450 enzymes (CYPs) play an essential role in this process, in vitro drug metabolism of four human CYP-specific substrates, i.e. dextromethorphan (DXM), diclofenac (DIC), testosterone (TST) and midazolam (MDZ) was investigated in adult male and female zebrafish, and in zebrafish embryos and larvae up to 120hours post-fertilization. Substrate depletion and production of their respective metabolites were measured using tandem quadrupole UPLC-MS/MS. Human liver microsomes were used as positive control. Adult zebrafish produced the two major human metabolites of DIC and DXM. For DIC the metabolite ratio was similar to that in man, whereas it was different for DXM. For TST, the major human metabolite could not be detected and MDZ was not metabolized. No sex-related differences were detected, except for the higher TST depletion rate in adult females. Zebrafish embryos and larvae showed no or only low biotransformation capacity. In conclusion, in vitro CYP-mediated drug metabolism in adult zebrafish shows differences compared to man and appears to be lacking in the early zebrafish life stages. As CYP-mediated drug metabolism in zebrafish may not be predictive for the one in man, we recommend including the zebrafish in metabolic stability testing of new compounds when considering non-clinical species for human risk assessment.

KEYWORDS:

Cytochrome; LC-MS; Microsomes; Ontogeny; Sex; Zebrafish

PMID:
28506817
DOI:
10.1016/j.tiv.2017.05.009
[Indexed for MEDLINE]

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