Silva Bárbara, Rodrigues Joana Saraiva, Almeida Ana Sofia, Lima Ana Rita, Fernandes Carla, Guedes de Pinho Paula, Miranda Joana Paiva, Remião Fernando
Associate Laboratory i4HB-Institute for Health and Bioeconomy, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Pharmaceuticals (Basel). 2022 Mar 17;15(3):368. doi: 10.3390/ph15030368.
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 -(-)-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; -(+)-methylone and -(-)-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.
戊二酮和甲酮在毒代动力学和毒效动力学过程中可表现出立体选择性。同样，它们在尚未评估的代谢过程中的手性识别可能导致不同的代谢谱及随后的肝毒性作用。因此，本研究的目的是首次使用生理相关的体外模型评估戊二酮和甲酮对映体的肝脏细胞毒性和代谢谱。在三维（3D-HLCs）和二维（2D-HLCs）条件下培养的人干细胞衍生的类肝细胞（HLCs）中，观察到这些化合物的肝毒性呈浓度依赖性。另一方面，仅在3D-HLCs中的戊二酮（1 mM）显示出对映选择性，其中-(-)-戊二酮细胞毒性最大。此外，代谢谱最初在人肝微粒体（HLM）中进行评估，并通过气相色谱-质谱联用（GC-MS）技术在3D-HLCs和2D-HLCs中进一步证实。甲酮和戊二酮的对映体显示出不同的优先代谢途径，产生不同的代谢产物；-(+)-甲酮和-(-)-戊二酮是代谢最多的对映体。总之，结果表明戊二酮和甲酮在代谢过程中具有对映选择性，戊二酮在细胞毒性方面具有对映选择性。
