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A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

2021-02-22Journal article Open access
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dc.contributor.authorSerras, Ana S.
dc.contributor.authorRodrigues, Joana S.
dc.contributor.authorCipriano, Madalena
dc.contributor.authorRodrigues, Armanda V.
dc.contributor.authorOliveira, Nuno G
dc.contributor.authorMiranda, Joana P
dc.date.accessioned2022-04-12T15:09:53Z
dc.date.available2022-04-12T15:09:53Z
dc.date.issued2021-02-22
dc.date.updated2022-02-24T12:48:08Z
dc.description.abstractThe poor predictability of human liver toxicity is still causing high attrition rates of drug candidates in the pharmaceutical industry at the non-clinical, clinical, and post-marketing authorization stages. This is in part caused by animal models that fail to predict various human adverse drug reactions (ADRs), resulting in undetected hepatotoxicity at the non-clinical phase of drug development. In an effort to increase the prediction of human hepatotoxicity, different approaches to enhance the physiological relevance of hepatic in vitro systems are being pursued. Three-dimensional (3D) or microfluidic technologies allow to better recapitulate hepatocyte organization and cell-matrix contacts, to include additional cell types, to incorporate fluid flow and to create gradients of oxygen and nutrients, which have led to improved differentiated cell phenotype and functionality. This comprehensive review addresses the drug-induced hepatotoxicity mechanisms and the currently available 3D liver in vitro models, their characteristics, as well as their advantages and limitations for human hepatotoxicity assessment. In addition, since toxic responses are greatly dependent on the culture model, a comparative analysis of the toxicity studies performed using two-dimensional (2D) and 3D in vitro strategies with recognized hepatotoxic compounds, such as paracetamol, diclofenac, and troglitazone is performed, further highlighting the need for harmonization of the respective characterization methods. Finally, taking a step forward, we propose a roadmap for the assessment of drugs hepatotoxicity based on fully characterized fit-for-purpose in vitro models, taking advantage of the best of each model, which will ultimately contribute to more informed decision-making in the drug development and risk assessment fields.pt_PT
dc.description.sponsorshipThis research has been supported by FCT (Portugal) through the research grants and scholarship PTDC/MED-TOX/29183/2017, UIDB/04138/2020, UIDP/04138/2020, and SFRH/BD/144130/2019 to JR and by the H2020, European Commission, though the MSCA-IF-EF-ST – Standard EF to MC (GA-845147-LIV-AD-ON-A-CHIP). Conflict of Interestpt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationSerras AS, Rodrigues JS, Cipriano M, Rodrigues AV, Oliveira NG, Miranda JP. A critical perspective on 3d liver models for drug metabolism and toxicology studies. Frontiers in Cell and Developmental Biology [Internet]. 2021;9:626805. Disponível em: https://www.frontiersin.org/article/10.3389/fcell.2021.626805pt_PT
dc.identifier.doihttps://doi.org/10.3389/fcell.2021.626805pt_PT
dc.identifier.issn2296-634X
dc.identifier.slugcv-prod-2244360
dc.identifier.urihttp://hdl.handle.net/10451/52314
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontierspt_PT
dc.relationGA-845147-LIV-AD-ON-A-CHIPpt_PT
dc.relationUnderstanding the underlying mechanisms by which mesenchymal stem cells promote liver regeneration: the specific role of exosomes
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationUnravelling the therapeutic effect of hnMSCs in an in vitro hepatic disease model of insulin resistance using hepatocytelike cells and Kupffer cells
dc.relation.publisherversionhttps://www.frontiersin.org/articles/10.3389/fcell.2021.626805pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectin vitro liver modelpt_PT
dc.subjectfit-for-purpose modelspt_PT
dc.subjecthepatotoxicitypt_PT
dc.subjectparacetamolpt_PT
dc.subjectdiclofenacpt_PT
dc.subjecttroglitazonept_PT
dc.subjectthree-dimensional culturept_PT
dc.titleA Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studiespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleUnderstanding the underlying mechanisms by which mesenchymal stem cells promote liver regeneration: the specific role of exosomes
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleUnravelling the therapeutic effect of hnMSCs in an in vitro hepatic disease model of insulin resistance using hepatocytelike cells and Kupffer cells
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-TOX%2F29183%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FDTP%2F04138%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F144130%2F2019/PT
oaire.citation.startPage626805pt_PT
oaire.citation.titleFrontiers in Cell and Developmental Biologypt_PT
oaire.citation.volume9pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
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person.familyNameSerras
person.familyNameRodrigues
person.familyNameOliveira
person.familyNameMiranda
person.givenNameAna
person.givenNameJoana
person.givenNameNuno
person.givenNameJoana P G
person.identifier793336
person.identifier666699
person.identifier507820
person.identifier.ciencia-idB41D-2E23-CD07
person.identifier.ciencia-id001A-6278-C231
person.identifier.orcid0000-0002-7941-9511
person.identifier.orcid0000-0002-1772-9813
person.identifier.orcid0000-0001-6114-6829
person.identifier.orcid0000-0002-7804-4068
person.identifier.ridA-7407-2014
person.identifier.ridJ-3698-2013
person.identifier.scopus-author-id7005130391
person.identifier.scopus-author-id12798235300
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.cv.cienciaid001A-6278-C231 | Joana Paiva Gomes Miranda
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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