Enantioselectivity of Pentedrone and Methylone on Metabolic Profiling in 2D and 3D Human Hepatocyte-like Cells

Silva, Bárbara; Rodrigues, Joana Saraiva; Almeida, Ana Sofia; Lima, Ana Rita; Fernandes, Carla; Guedes de Pinho, Paula; Miranda, Joana Paiva; Remião, Fernando

doi:10.3390/ph15030368

Title: Enantioselectivity of Pentedrone and Methylone on Metabolic Profiling in 2D and 3D Human Hepatocyte-like Cells

Journal Article · Thu Mar 17 00:00:00 EDT 2022 · Pharmaceuticals

DOI:https://doi.org/10.3390/ph15030368· OSTI ID:1855896

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Pentedrone and methylone can express stereoselectivity in toxicokinetic and toxicodynamic processes. Similarly, their chiral discrimination in metabolism, which was not yet evaluated, can result in different metabolic profiles and subsequent hepatotoxic effects. Therefore, the aim of this work was to assess, for the first time, both the hepatic cytotoxic and metabolic profile of pentedrone and methylone enantiomers using physiologically relevant in vitro models. The hepatotoxicity of these compounds was observed in a concentration-dependent manner in human stem-cell-derived hepatocyte-like cells (HLCs) cultured under 3D (3D-HLCs) and 2D (2D-HLCs) conditions. Enantioselectivity, on the other hand, was only shown for pentedrone (1 mM) in 3D-HLCs, being R-(−)-pentedrone the most cytotoxic. Furthermore, the metabolic profile was initially evaluated in human liver microsomes (HLM) and further demonstrated in 3D-HLCs and 2D-HLCs applying a gas chromatography coupled to a mass spectrometer (GC–MS) technique. Methylone and pentedrone showed distinct and preferential metabolic routes for their enantiomers, resulting in the production of differentiated metabolites; R-(+)-methylone and R-(−)-pentedrone are the most metabolized enantiomers. In conclusion, the results demonstrated enantioselectivity for pentedrone and methylone in the metabolic processes, with enantioselectivity in cytotoxicity for pentedrone.

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Sponsoring Organization:: USDOE Office of Energy Efficiency and Renewable Energy (EERE), Transportation Office. Fuel Cell Technologies Office

Grant/Contract Number:: UIDB/04423/2020 and UIDP/04423/2020; UIDB/04378/2020; PTDC/MED-TOX/29183/2017, SFRH/BD/144130/2019; UIDB/04138/2020 e UIDP/04138/2020

OSTI ID:: 1855896

Journal Information:: Pharmaceuticals, Journal Name: Pharmaceuticals Vol. 15 Journal Issue: 3; ISSN 1424-8247

Publisher:: MDPI AGCopyright Statement

Country of Publication:: Switzerland

Language:: English

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