PUBLICATION
In vitro CYP-mediated drug metabolism in the zebrafish (embryo) using human reference compounds
- Authors
- Saad, M., Matheeussen, A., Bijttebier, S., Verbueken, E., Pype, C., Casteleyn, C., Van Ginneken, C., Apers, S., Maes, L., Cos, P., Van Cruchten, S.
- ID
- ZDB-PUB-170517-12
- Date
- 2017
- Source
- Toxicology in vitro : an international journal published in association with BIBRA 42: 329-336 (Journal)
- Registered Authors
- Van Cruchten, Steven, Verbueken, Evy
- Keywords
- Cytochrome, LC-MS, Microsomes, Ontogeny, Sex, Zebrafish
- MeSH Terms
-
- Animals
- Biotransformation
- Cytochrome P-450 Enzyme System/metabolism*
- Dextromethorphan/metabolism*
- Diclofenac/metabolism*
- Embryo, Nonmammalian/metabolism
- Female
- Humans
- Male
- Microsomes, Liver/metabolism
- Midazolam/metabolism*
- Testosterone/metabolism*
- Zebrafish/metabolism*
- PubMed
- 28506817 Full text @ Toxicol. In Vitro
Citation
Saad, M., Matheeussen, A., Bijttebier, S., Verbueken, E., Pype, C., Casteleyn, C., Van Ginneken, C., Apers, S., Maes, L., Cos, P., Van Cruchten, S. (2017) 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. 42:329-336.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping