Cytotoxicity, metabolism, and isozyme mapping of the synthetic cannabinoids JWH-200, A-796260, and 5F-EMB-PINACA studied by means of in vitro systems
Autor: | Tanja M. Gampfer, Markus R. Meyer, Veit Flockerzi, Lea Wagmann, Anouar Belkacemi |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Cyclopropanes
HepG2 medicine.drug_class Synthetic cannabinoids Health Toxicology and Mutagenesis Cytotoxicity Morpholines Carboxamide Isozyme mapping Toxicology Isozyme Imaging Hydroxylation chemistry.chemical_compound Tandem Mass Spectrometry Morpholine medicine Humans Chemistry Cannabinoids In vitro toxicology General Medicine Hep G2 Cells Isoenzymes In Vitro Systems Metabolism Biochemistry Microsome Microsomes Liver Drug metabolism medicine.drug Chromatography Liquid |
Zdroj: | Archives of Toxicology |
ISSN: | 1432-0738 0340-5761 |
Popis: | Intake of synthetic cannabinoids (SC), one of the largest classes of new psychoactive substances, was reported to be associated with acute liver damage but information about their hepatotoxic potential is limited. The current study aimed to analyze the hepatotoxicity including the metabolism-related impact of JWH-200, A-796260, and 5F-EMB-PINACA in HepG2 cells allowing a tentative assessment of different SC subclasses. A formerly adopted high-content screening assay (HCSA) was optimized using a fully automated epifluorescence microscope. Metabolism-mediated effects in the HCSA were additionally investigated using the broad CYP inhibitor 1-aminobenzotriazole. Furthermore, phase I metabolites and isozymes involved were identified by in vitro assays and liquid chromatography–high-resolution tandem mass spectrometry. A strong cytotoxic potential was observed for the naphthoylindole SC JWH-200 and the tetramethylcyclopropanoylindole compound A-796260, whereas the indazole carboxamide SC 5F-EMB-PINACA showed moderate effects. Numerous metabolites, which can serve as analytical targets in urine screening procedures, were identified in pooled human liver microsomes. Most abundant metabolites of JWH-200 were formed by N-dealkylation, oxidative morpholine cleavage, and oxidative morpholine opening. In case of A-796260, most abundant metabolites included an oxidative morpholine cleavage, oxidative morpholine opening, hydroxylation, and dihydroxylation followed by dehydrogenation. Most abundant 5F-EMB-PINACA metabolites were generated by ester hydrolysis plus additional steps such as oxidative defluorination and hydroxylation. To conclude, the data showed that a hepatotoxicity of the investigated SC cannot be excluded, that metabolism seems to play a minor role in the observed effects, and that the extensive phase I metabolism is mediated by several isozymes making interaction unlikely. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03148-3. |
Databáze: | OpenAIRE |
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