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

Autor: Chris Van Ginneken, Steven Van Cruchten, Els Van Peer, Christophe Casteleyn, Casper Pype, Evy Verbueken, Moayad A. Saad, Derek Alsop, Joanna Y. Wilson
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Embryo
Nonmammalian
CYP3A
Veterinary medicine
Metabolite
Developmental toxicity
Firefly Luciferin
010501 environmental sciences
Pharmacology
01 natural sciences
and biotransformation
Substrate Specificity
lcsh:Chemistry
chemistry.chemical_compound
Biotransformation
Cytochrome P-450 CYP3A
Zebrafish
lcsh:QH301-705.5
Spectroscopy
Recombination
Genetic
biology
in vitro
General Medicine
Computer Science Applications
Chemistry
Ketoconazole
Biochemistry
embryonic structures
zebrafish
embryo
development
cytochrome P450
activity
Microsomes
Liver
Female
animal structures
Embryonic Development
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
Oxazines
Animals
Humans
Physical and Theoretical Chemistry
Biology
Molecular Biology
0105 earth and related environmental sciences
Organic Chemistry
Cytochrome P450
biology.organism_classification
In vitro
030104 developmental biology
chemistry
lcsh:Biology (General)
lcsh:QD1-999
Molecular Probes
biology.protein
Microsome
Zdroj: International Journal of Molecular Sciences, Vol 18, Iss 1, p 217 (2017)
International journal of molecular sciences
International Journal of Molecular Sciences
International Journal of Molecular Sciences; Volume 18; Issue 1; Pages: 217
ISSN: 1422-0067
Popis: 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 enzymesin 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.
Databáze: OpenAIRE
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