{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T21:43:47Z","timestamp":1773351827538,"version":"3.50.1"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:00:00Z","timestamp":1647475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT","award":["UIDB\/04423\/2020 and UIDP\/04423\/2020"],"award-info":[{"award-number":["UIDB\/04423\/2020 and UIDP\/04423\/2020"]}]},{"name":"FCT","award":["UIDB\/04378\/2020"],"award-info":[{"award-number":["UIDB\/04378\/2020"]}]},{"name":"FCT","award":["PTDC\/MED-TOX\/29183\/2017, SFRH\/BD\/144130\/2019"],"award-info":[{"award-number":["PTDC\/MED-TOX\/29183\/2017, SFRH\/BD\/144130\/2019"]}]},{"name":"FCT","award":["UIDB\/04138\/2020 e UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020 e UIDP\/04138\/2020"]}]},{"name":"University of Porto\/ Faculty of Medicine University of Porto through FSE\u2014Fundo Social Europeu, NORTE2020\u2014Programa Operacional Regional do Norte","award":["NORTE-08-5369-FSE-000011"],"award-info":[{"award-number":["NORTE-08-5369-FSE-000011"]}]},{"name":"Erasmus+ Programme of the European Union","award":["Project no. 2020-1-CZ01-KA203-078218"],"award-info":[{"award-number":["Project no. 2020-1-CZ01-KA203-078218"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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-(\u2212)-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\u2013MS) technique. Methylone and pentedrone showed distinct and preferential metabolic routes for their enantiomers, resulting in the production of differentiated metabolites; R-(+)-methylone and R-(\u2212)-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.<\/jats:p>","DOI":"10.3390\/ph15030368","type":"journal-article","created":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T21:34:27Z","timestamp":1647812067000},"page":"368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Enantioselectivity of Pentedrone and Methylone on Metabolic Profiling in 2D and 3D Human Hepatocyte-like Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7399-0197","authenticated-orcid":false,"given":"B\u00e1rbara","family":"Silva","sequence":"first","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"UCIBIO-REQUIMTE, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1772-9813","authenticated-orcid":false,"given":"Joana Saraiva","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (imed), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6826-1854","authenticated-orcid":false,"given":"Ana Sofia","family":"Almeida","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1439-770X","authenticated-orcid":false,"given":"Ana Rita","family":"Lima","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"UCIBIO-REQUIMTE, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0940-9163","authenticated-orcid":false,"given":"Carla","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental (CIIMAR), Universidade do Porto, Avenida General Norton de Matos, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7395-5700","authenticated-orcid":false,"given":"Paula","family":"Guedes de Pinho","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"UCIBIO-REQUIMTE, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7804-4068","authenticated-orcid":false,"given":"Joana Paiva","family":"Miranda","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (imed), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"UCIBIO-REQUIMTE, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"key":"ref_1","first-page":"268","article-title":"Synthetic cathinones related fatalities: An update","volume":"22","author":"Zaami","year":"2018","journal-title":"Eur. 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