Repository logo
 
Publication

The 2-hydroxy-nevirapine metabolite as a candidate for boosting apolipoprotein A1 and for modulating anti-HDL antibodies

2021-03-16Journal article Restricted access
Simple item page
dc.contributor.authorMarinho, Aline T.
dc.contributor.authorBatuca, Joana R.
dc.contributor.authorMiranda, Joana P.
dc.contributor.authorCaixas, Umbelina
dc.contributor.authorDias, Clara G.
dc.contributor.authorBranco, Teresa
dc.contributor.authorSoto, Karina
dc.contributor.authorPinheiro, Pedro
dc.contributor.authorBourbon, Mafalda
dc.contributor.authorMarques, M. Matilde
dc.contributor.authorAntunes, Alexandra M.
dc.contributor.authorMonteiro, Emília C.
dc.contributor.authorPereira, Sofia A.
dc.date.accessioned2022-02-01T16:13:25Z
dc.date.available2022-02-01T16:13:25Z
dc.date.issued2021-03-16
dc.description.abstractThe antiretroviral nevirapine (NVP) is associated to a reduction of atherosclerotic lesions and increases in high-density lipoprotein (HDL)-cholesterol. Despite being a hepatotoxic drug, which forbids its re-purposing to other therapeutic areas, not all NVP metabolites have the same potential to induce toxicity. Our aim was to investigate the effects of NVP and its metabolites in an exploratory study, towards the identification of a candidate to boost HDL. A pilot prospective (n = 11) and a cross-sectional (n = 332) clinical study were performed with the following endpoints: HDL-cholesterol and apolipoprotein A1 (ApoA1) levels, anti-HDL and anti-ApoA1 antibodies titers, paraoxonase, arylesterase and lactonase activities of paraoxonase-1, and NVP's metabolite profile. NVP treatment increased HDL-cholesterol, ApoA1 and paraoxonase-1 activities, and lowered anti-HDL and anti-ApoA1 titers. In the prospective study, the temporal modulation induced by NVP was different for each HDL-related endpoint. The first observation was a decrease in the anti-HDL antibodies titers. In the cross-sectional study, the lower titers of anti-HDL antibodies were associated to the proportion of 2-hydroxy-NVP (p = 0.03). In vitro models of hepatocytes were employed to clarify the individual contribution of NVP's metabolites for ApoA1 modulation. Long-term incubations of NVP and 2-hydroxy-NVP in the metabolically competent 3D model caused an increase in ApoA1 reaching 43 % (p < 0.05) and 86 % (p < 0.001), respectively. These results support the contribution of drug biotransformation for NVP-induced HDL modulation, highlighting the role of 2-hydroxy-NVP as ApoA1 booster and its association to lower anti-HDL titers. This biotransformation-guided approach allowed us to identify a non-toxic NVP metabolite as a candidate for targeting HDL.pt_PT
dc.description.sponsorshipThe research work was funded by Fundação para a Ciência e a Tecnologia (FCT) Portugal [grant references: SFRH/BD/92191/2013, PhD grant to ATM; CEECIND/02001/2017 grant to AMA; EXPL/DTP-FTO/0204/2012; RECI/QEQ-MED/0330/2012; UID/QUI/00100/2019; PTDC/MED-TOX/29183/2017; UID/DTP/04138/2019; UID/QUI/ 00100/2013; iNOVA4Health - UID/Multi/04462/2013, a program financially supported by FCT/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement].pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPharmacol Res. 2021 Mar;165:105446. doi: 10.1016/j.phrs.2021.105446. Epub 2021 Jan 27.pt_PT
dc.identifier.doi10.1016/j.phrs.2021.105446pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7907
dc.language.isoengpt_PT
dc.publisherElsevier/ Academic Presspt_PT
dc.relationCEECIND/02001/2017pt_PT
dc.relationTEACHING AN OLD DRUG NEW TRICKS: RE-PROFILING OF NEVIRAPINE AS AN HDL MODULATOR
dc.relationCentro de Química Estrutural
dc.relationUnderstanding the underlying mechanisms by which mesenchymal stem cells promote liver regeneration: the specific role of exosomes
dc.relationResearch Institute for Medicines
dc.relation.publisherversionhttps://pubmed.ncbi.nlm.nih.gov/33515705/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subject12-hydroxy-nevirapine (CID 453338)pt_PT
dc.subject2-Hydroxy-nevirapinept_PT
dc.subject2-hydroxy-nevirapine (CID 10850461)pt_PT
dc.subjectAnti-HDL Antibodiespt_PT
dc.subjectApolipoprotein A1pt_PT
dc.subjectDrug Biotransformationpt_PT
dc.subjectHigh-density Lipoproteinpt_PT
dc.subjectNevirapinept_PT
dc.subjectNevirapine (CID 4463)pt_PT
dc.subjectDoenças Cardio e Cérebro-vascularespt_PT
dc.titleThe 2-hydroxy-nevirapine metabolite as a candidate for boosting apolipoprotein A1 and for modulating anti-HDL antibodiespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTEACHING AN OLD DRUG NEW TRICKS: RE-PROFILING OF NEVIRAPINE AS AN HDL MODULATOR
oaire.awardTitleCentro de Química Estrutural
oaire.awardTitleUnderstanding the underlying mechanisms by which mesenchymal stem cells promote liver regeneration: the specific role of exosomes
oaire.awardTitleResearch Institute for Medicines
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F92191%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/EXPL%2FDTP-FTO%2F0204%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/RECI%2FQEQ-MED%2F0330%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FQUI%2F00100%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-TOX%2F29183%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FDTP%2F04138%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04462%2F2013/PT
oaire.citation.startPage105446pt_PT
oaire.citation.titlePharmacological Researchpt_PT
oaire.citation.volume165pt_PT
oaire.fundingStreamOE
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream5876
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.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
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationade5b37a-53ef-4cec-9260-7a0823fc5926
relation.isProjectOfPublication52962bee-7315-4c14-8dfe-93103c950b60
relation.isProjectOfPublication46b679be-28f2-4c4b-a53e-e6b654bf46ce
relation.isProjectOfPublicationf2e67b0d-b91b-48d6-b9c6-b824ac9fd67f
relation.isProjectOfPublicationf196a9e6-4ef0-49b6-a291-9e791643c741
relation.isProjectOfPublication206cdeaa-76a3-43a8-81c3-589822c1adb5
relation.isProjectOfPublicationf7e7f835-30c4-427e-a9ee-d5940c3e2710
relation.isProjectOfPublication.latestForDiscovery52962bee-7315-4c14-8dfe-93103c950b60

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
The 2-hydroxy-nevirapine metabolite as a candidate for boosting apolipoprotein A1 and for modulating anti-HDL antibodies.pdf
Size:
2.58 MB
Format:
Adobe Portable Document Format
Download

Collections

DPSPDNT - Artigos em revistas internacionais