PUBLICATION

Induction of Liver Size Reduction in Zebrafish Larvae by the Emerging Synthetic Cannabinoid 4F-MDMB-BINACA and Its Impact on Drug Metabolism

Authors
Park, Y.M., Dahlem, C., Meyer, M.R., Kiemer, A.K., Müller, R., Herrmann, J.
ID
ZDB-PUB-220226-20
Date
2022
Source
Molecules   27(4): (Journal)
Registered Authors
Keywords
cannabinoid receptors (CB1 and CB2), drug metabolism, hepatotoxicity, mass spectrometry imaging (MSI), methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′N-5F-ADB), methyl 2-[1-(4-fluorobutyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoate (4F-MDMB-BINACA), microinjection, morpholino oligonucleotides, synthetic cannabinoid (SC), zebrafish larvae model
MeSH Terms
  • Molecular Structure
  • Cannabinoids/chemical synthesis
  • Cannabinoids/chemistry
  • Cannabinoids/pharmacology*
  • Organ Size/drug effects
  • Liver/drug effects*
  • Liver/metabolism*
  • Liver/pathology
  • Zebrafish
  • Receptors, Cannabinoid/metabolism
  • Inactivation, Metabolic/drug effects*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Metabolic Networks and Pathways
  • Larva
  • Animals
  • Chemical Phenomena
(all 16)
PubMed
35209079 Full text @ Molecules
Abstract
Zebrafish (ZF; Danio rerio) larvae have become a popular in vivo model in drug metabolism studies. Here, we investigated the metabolism of methyl 2-[1-(4-fluorobutyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoate (4F-MDMB-BINACA) in ZF larvae after direct administration of the cannabinoid via microinjection, and we visualized the spatial distributions of the parent compound and its metabolites by mass spectrometry imaging (MSI). Furthermore, using genetically modified ZF larvae, the role of cannabinoid receptor type 1 (CB1) and type 2 (CB2) on drug metabolism was studied. Receptor-deficient ZF mutant larvae were created using morpholino oligonucleotides (MOs), and CB2-deficiency had a critical impact on liver development of ZF larva, leading to a significant reduction of liver size. A similar phenotype was observed when treating wild-type ZF larvae with 4F-MDMB-BINACA. Thus, we reasoned that the cannabinoid-induced impaired liver development might also influence its metabolic function. Studying the metabolism of two synthetic cannabinoids, 4F-MDMB-BINACA and methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7'N-5F-ADB), revealed important insights into the in vivo metabolism of these compounds and the role of cannabinoid receptor binding.
Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gz15TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    cnr1MO5-cnr1MRPHLNO
    cnr2MO2-cnr2MRPHLNO
    1 - 2 of 2
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    Fish
    No data available
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    DsRedEFGDsRed
    EGFPEFGEGFP
    1 - 2 of 2
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    Mapping
    No data available
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    Citation
    Park, Y.M., Dahlem, C., Meyer, M.R., Kiemer, A.K., Müller, R., Herrmann, J. (2022) Induction of Liver Size Reduction in Zebrafish Larvae by the Emerging Synthetic Cannabinoid 4F-MDMB-BINACA and Its Impact on Drug Metabolism. Molecules. 27(4):.