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GC–MS metabolomics reveals disturbed metabolic pathways in primary mouse hepatocytes exposed to subtoxic levels of 3,4-methylenedioxymethamphetamine (MDMA)

2018Journal article Restricted access
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dc.contributor.authorAraújo, Ana Margarida
dc.contributor.authorBastos, Maria de Lourdes
dc.contributor.authorFernandes, Eduarda
dc.contributor.authorCarvalho, Félix
dc.contributor.authorCarvalho, Márcia
dc.contributor.authorGuedes de Pinho, Paula
dc.date.accessioned2021-06-30T11:03:17Z
dc.date.available2021-06-30T11:03:17Z
dc.date.issued2018
dc.description.abstract3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a well-known hepatotoxic drug. Although its toxicity has been thoroughly studied at high concentrations, there is still insufficient knowledge on possible alterations of cell function at subtoxic concentrations, which are in fact more representative concentrations of intoxication scenarios. In this study, a gas chromatography-mass spectrometry (GC-MS) metabolomics approach was used to investigate the metabolic changes in primary mouse hepatocytes (PMH) exposed to two subtoxic concentrations of MDMA (LC01 and LC10) for 24 h. Metabolomic profiling of both intracellular metabolites and volatile metabolites in the extracellular medium of PMH was performed. Multivariate analysis showed that the metabolic pattern of cells exposed to MDMA discriminates from the controls in a concentration-dependent manner. Exposure to LC10 MDMA induces a significant increase in some intracellular metabolites, including oleic acid and palmitic acid, and a decrease in glutamate, aspartate, 5-oxoproline, fumarate, malate, phosphoric acid, α-ketoglutarate and citrate. Extracellular metabolites such as acetophenone, formaldehyde, pivalic acid, glyoxal and 2-butanone were found significantly increased after exposure to MDMA, compared to controls, whereas 4-methylheptane, 2,4-dimethyl-1-heptene, nonanal, among others, were found significantly decreased. The panel of discriminatory metabolites is mainly involved in tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamate metabolism, antioxidant defenses and possibly changes in the liver enzyme machinery. Overall, these results highlight the potential of the intra- and extracellular metabolome to study alterations triggered by subtoxic concentrations of MDMA in hepatic cell functions, which represents a more realistic appraisal of early toxicity events posed by exposure to this drug. In addition, these results also revealed some metabolites that may be used as potential biomarkers indicative of early events in the hepatotoxicity induced by MDMA.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1007/s00204-018-2314-9pt_PT
dc.identifier.eissn1432-0738
dc.identifier.issn0340-5761
dc.identifier.urihttp://hdl.handle.net/10284/9980
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relationThis work received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007728) and National Funds (FCT/MEC, Fundação para a Ciência e a Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/04378/2013. The study is a result of the project NORTE-01-0145-FEDER-000024, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement (DESign BIOtecHealth—New Technologies for three Health Challenges of Modern Societies: Diabetes, Drug Abuse and Kidney Diseases), through the European Regional Development Fund (ERDF). A. M. Araújo thanks to FCT for her PhD fellowship (SFRH/BD/107708/2015) and M. Carvalho also acknowl- edges FCT through the UID/MULTI/04546/2016 project.pt_PT
dc.subjectMDMApt_PT
dc.subjectMetabolomicspt_PT
dc.subjectPrimary mouse hepatocytespt_PT
dc.subjectHepatotoxicitypt_PT
dc.subjectSubtoxic concentrationspt_PT
dc.titleGC–MS metabolomics reveals disturbed metabolic pathways in primary mouse hepatocytes exposed to subtoxic levels of 3,4-methylenedioxymethamphetamine (MDMA)pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage3323pt_PT
oaire.citation.issue11pt_PT
oaire.citation.startPage3307pt_PT
oaire.citation.titleArchives of Toxicologypt_PT
oaire.citation.volume92pt_PT
person.familyNameCarvalho
person.givenNameMarcia
person.identifier2017111
person.identifier.ciencia-id8B10-171E-E63E
person.identifier.orcid0000-0001-9884-4751
person.identifier.ridD-5999-2013
person.identifier.scopus-author-id7201413997
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication3837b828-ba57-47f7-a811-cce65e4922c6
relation.isAuthorOfPublication.latestForDiscovery3837b828-ba57-47f7-a811-cce65e4922c6

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