Commemorating 85 years of publications on Cannabis by Archives of Toxicology

Bolt, Hermann M.; Hengstler, Jan G.

doi:10.1007/s00204-021-03079-z

Cited by 1 publication

(1 citation statement)

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“…The ongoing emergence of new psychoactive substances (NPS) on the drugs of abuse market remains an analytical challenge for clinical and forensic toxicologists. Moreover, numerous case reports of intoxications or even deaths after intake of synthetic cannabinoids (SC) demonstrate the threat on public health (Adamowicz et al 2019;Bolt and Hengstler 2021;Hvozdovich et al 2020). Some reports associated their intake with liver failure, but knowledge about their hepatotoxic potential is sparse or even unknown (Solimini et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity, metabolism, and isozyme mapping of the synthetic cannabinoids JWH-200, A-796260, and 5F-EMB-PINACA studied by means of in vitro systems

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%