PUBLICATION
Developmental Toxicity and Biotransformation of Two Anti-Epileptics in Zebrafish Embryos and Early Larvae
- Authors
- Bars, C., Hoyberghs, J., Valenzuela, A., Buyssens, L., Ayuso, M., Van Ginneken, C., Labro, A.J., Foubert, K., Van Cruchten, S.J.
- ID
- ZDB-PUB-211214-21
- Date
- 2021
- Source
- International Journal of Molecular Sciences 22(23): (Journal)
- Registered Authors
- Van Cruchten, Steven
- Keywords
- bioactivation, developmental toxicology, drug metabolism, embryo, in vitro, zebrafish
- MeSH Terms
-
- Animals
- Anticonvulsants/toxicity*
- Biotransformation*
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/pathology*
- Embryonic Development*
- Humans
- Larva/drug effects
- Larva/growth & development*
- Microsomes, Liver/drug effects
- Microsomes, Liver/pathology*
- Organogenesis*
- Rabbits
- Rats
- Rats, Sprague-Dawley
- Teratogens/toxicity
- Zebrafish
- PubMed
- 34884510 Full text @ Int. J. Mol. Sci.
Citation
Bars, C., Hoyberghs, J., Valenzuela, A., Buyssens, L., Ayuso, M., Van Ginneken, C., Labro, A.J., Foubert, K., Van Cruchten, S.J. (2021) Developmental Toxicity and Biotransformation of Two Anti-Epileptics in Zebrafish Embryos and Early Larvae. International Journal of Molecular Sciences. 22(23):.
Abstract
The zebrafish (Danio rerio) embryo is gaining interest as a bridging tool between in-vitro and in-vivo developmental toxicity studies. However, cytochrome P450 (CYP)-mediated drug metabolism in this model is still under debate. Therefore, we investigated the potential of zebrafish embryos and larvae to bioactivate two known anti-epileptics, carbamazepine (CBZ) and phenytoin (PHE), to carbamazepine-10,11-epoxide (E-CBZ) and 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), respectively. First, zebrafish were exposed to CBZ, PHE, E-CBZ and HPPH from 5¼- to 120-h post fertilization (hpf) and morphologically evaluated. Second, the formations of E-CBZ and HPPH were assessed in culture medium and in whole-embryo extracts at different time points by targeted LC-MS. Finally, E-CBZ and HPPH formation was also assessed in adult zebrafish liver microsomes and compared with those of human, rat, and rabbit. The present study showed teratogenic effects for CBZ and PHE, but not for E-CBZ and HPPH. No HPPH was detected during organogenesis and E-CBZ was only formed at the end of organogenesis. E-CBZ and HPPH formation was also very low-to-negligible in adult zebrafish compared with the mammalian species. As such, other metabolic pathways than those of mammals are involved in the bioactivation of CBZ and PHE, or, these anti-epileptics are teratogens and do not require bioactivation in the zebrafish.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping