Cytotoxicity, metabolism, and isozyme mapping of the synthetic cannabinoids JWH-200, A-796260, and 5F-EMB-PINACA studied by means of in vitro systems.
Cytotoxicity
HepG2
Imaging
Isozyme mapping
Metabolism
Synthetic cannabinoids
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
05
07
2021
accepted:
19
08
2021
pubmed:
29
8
2021
medline:
9
2
2022
entrez:
28
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34453555
doi: 10.1007/s00204-021-03148-3
pii: 10.1007/s00204-021-03148-3
pmc: PMC8492589
doi:
Substances chimiques
(1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone
0
Cannabinoids
0
Cyclopropanes
0
Isoenzymes
0
Morpholines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3539-3557Subventions
Organisme : deutsche forschungsgemeinschaft
ID : SFB 894
Organisme : deutsche forschungsgemeinschaft
ID : INST 256/414-1 FUGG
Informations de copyright
© 2021. The Author(s).
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