{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:04:37Z","timestamp":1770984277621,"version":"3.50.1"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T00:00:00Z","timestamp":1591142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MED-TOX\/29183\/2017"],"award-info":[{"award-number":["PTDC\/MED-TOX\/29183\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The need for competent in vitro liver models for toxicological assessment persists. The differentiation of stem cells into hepatocyte-like cells (HLC) has been adopted due to its human origin and availability. Our aim was to study the usefulness of an in vitro 3D model of mesenchymal stem cell-derived HLCs. 3D spheroids (3D-HLC) or monolayer (2D-HLC) cultures of HLCs were treated with the hepatotoxic drug nevirapine (NVP) for 3 and 10 days followed by analyses of Phase I and II metabolites, biotransformation enzymes and drug transporters involved in NVP disposition. To ascertain the toxic effects of NVP and its major metabolites, the changes in the glutathione net flux were also investigated. Phase I enzymes were induced in both systems yielding all known correspondent NVP metabolites. However, 3D-HLCs showed higher biocompetence in producing Phase II NVP metabolites and upregulating Phase II enzymes and MRP7. Accordingly, NVP-exposure led to decreased glutathione availability and alterations in the intracellular dynamics disfavoring free reduced glutathione and glutathionylated protein pools. Overall, these results demonstrate the adequacy of the 3D-HLC model for studying the bioactivation\/metabolism of NVP representing a further step to unveil toxicity mechanisms associated with glutathione net flux changes.<\/jats:p>","DOI":"10.3390\/ijms21113998","type":"journal-article","created":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T04:36:09Z","timestamp":1591245369000},"page":"3998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Nevirapine Biotransformation Insights: An Integrated In Vitro Approach Unveils the Biocompetence and Glutathiolomic Profile of a Human Hepatocyte-Like Cell 3D Model"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6285-3434","authenticated-orcid":false,"given":"Madalena","family":"Cipriano","sequence":"first","affiliation":[{"name":"Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, 70569 Stuttgart, Germany"},{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Pedro F","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Centro de Qu\u00edmica Estrutural (CQE), Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal"}]},{"given":"Catarina O","family":"Sequeira","sequence":"additional","affiliation":[{"name":"Centro de Estudos de Doen\u00e7as Cr\u00f3nicas (CEDOC), NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1772-9813","authenticated-orcid":false,"given":"Joana S","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Nuno G","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1827-7369","authenticated-orcid":false,"given":"Alexandra M M","family":"Antunes","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural (CQE), Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal"}]},{"given":"Matilde","family":"Castro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7526-4962","authenticated-orcid":false,"given":"M Matilde","family":"Marques","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural (CQE), Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8456-9995","authenticated-orcid":false,"given":"Sofia A","family":"Pereira","sequence":"additional","affiliation":[{"name":"Centro de Estudos de Doen\u00e7as Cr\u00f3nicas (CEDOC), NOVA Medical School\/Faculdade de Ci\u00eancias M\u00e9dicas, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7804-4068","authenticated-orcid":false,"given":"Joana P","family":"Miranda","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1007\/s00204-013-1078-5","article-title":"Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME","volume":"87","author":"Godoy","year":"2013","journal-title":"Arch. 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