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

Toxicology in Vitro : an International Journal Published in Association with BIBRA
Moayad SaadSteven Van Cruchten

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 ...Continue Reading

Citations

Dec 21, 2018·Environmental Toxicology and Chemistry·Ellen D G MichielsDries Knapen
May 17, 2019·High-throughput·Jingshu Guo, Robert J Turesky
May 20, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Alena TierbachMarc J-F Suter
Nov 3, 2020·MethodsX·Jente HoyberghsSteven Van Cruchten
Jun 11, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Sebastian HoffmannKatya Tsaioun
Oct 19, 2019·Chemical Research in Toxicology·Steven CassarLeonard I Zon
Oct 30, 2021·Environmental Science and Pollution Research International·Jiarui LuYide He
Feb 23, 2020·Ecotoxicology and Environmental Safety·Ann-Kathrin LoerracherThomas Braunbeck

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