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

Molecules

Markus R. Meyer¹  Alexandra K. Kiemer²  Charlotte Dahlem²  Jennifer Herrmann³  Yu Mi Park³  Rolf Müller³ 

[1] Center for Molecular Signaling (PZMS), Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Experimental and Clinical Toxicology, Saarland University, 66421 Homburg, Germany;Department of Pharmacy, Pharmaceutical Biology, Campus C2 3, Saarland University, 66123 Saarbrücken, Germany;Helmholtz Centre for Infection Research, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E8 1, Saarland University, 66123 Saarbrücken, Germany;

关键词: zebrafish larvae model;    drug metabolism;    cannabinoid receptors (CB1 and CB2);    mass spectrometry imaging (MSI);    hepatotoxicity;    microinjection;   

DOI  :  10.3390/molecules27041290

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown