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Metabolism is required for the expression of ecstasy-induced cardiotoxicity in vitro

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dc.contributor.authorCarvalho, Márcia
dc.contributor.authorRemião, Fernando
dc.contributor.authorMilhazes, Nuno
dc.contributor.authorBorges, Fernanda
dc.contributor.authorFernandes, Eduarda
dc.contributor.authorMonteiro, Maria do Céu
dc.contributor.authorGonçalves, Maria José
dc.contributor.authorSeabra, Vítor
dc.contributor.authorAmado, Francisco
dc.contributor.authorCarvalho, Félix
dc.contributor.authorBastos, Maria de Lourdes
dc.date.accessioned2021-07-01T16:30:44Z
dc.date.available2021-07-01T16:30:44Z
dc.date.issued2004
dc.description.abstractCardiovascular complications associated with 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse have increasingly been reported. The indirect effect of MDMA mediated by a sustained high level of circulating biogenic amines may contribute to the cardiotoxic effects, but other factors, like the direct toxic effects of MDMA and its metabolites in cardiac cells, remain to be investigated. Thus, the objective of the present in vitro study was to evaluate the potential cardiotoxic effects of MDMA and its major metabolites 3,4-methylenedioxyamphetamine (MDA), N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA), and alpha-methyldopamine (alpha-MeDA) using freshly isolated adult rat cardiomyocytes. The cell suspensions were incubated with these compounds in the final concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 mM for 4 h. alpha-MeDA, N-Me-alpha-MeDA, and their respective aminochromes (oxidation products) were quantified in cell suspensions by HPLC-DAD. The toxic effects were evaluated at hourly intervals for 4 h by measuring the percentage of cells with normal morphology, glutathione (GSH), and glutathione disulfide (GSSG); intracellular Ca(2+), ATP, and ADP; and the cellular activities of glutathione peroxidase, glutathione reductase, and glutathione-S-transferase. No toxic effects were found after exposure of rat cardiomyocytes to MDMA or MDA at any of the tested concentrations for 4 h. In contrast, their catechol metabolites N-Me-alpha-MeDA and alpha-MeDA induced significant toxicity in rat cardiomyocytes. The toxic effects were characterized by a loss of normal cell morphology, which was preceded by a loss of GSH homeostasis due to conjugation of GSH with N-Me-alpha-MeDA and alpha-MeDA, sustained increase of intracellular Ca(2+) levels, ATP depletion, and decreases in the antioxidant enzyme activities. The oxidation of N-Me-alpha-MeDA and alpha-MeDA into the toxic compounds N-methyl-alpha-methyldopaminochrome and alpha-methyldopaminochrome, respectively, was also verified in cell suspensions incubated with these MDMA metabolites. The results obtained in this study provide evidence that the metabolism of MDMA into N-Me-alpha-MeDA and alpha-MeDA is required for the expression of MDMA-induced cardiotoxicity in vitro, being N-Me-alpha-MeDA the most toxic of the studied metabolites.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1021/tx049960fpt_PT
dc.identifier.eissn1520-5010
dc.identifier.issn0893-228X
dc.identifier.urihttp://hdl.handle.net/10284/10006
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Chemical Societypt_PT
dc.relationThis work was supported by Ph.D. grants from FCT (Praxis XXI/BD/20087/99 and Praxis XXI/BD/18520/98) and POCTI, Portugal, and by FEDER European Community funding (Project POCTI/ 36099/FCB/2000).pt_PT
dc.subject3,4-Methylenedioxyamphetaminept_PT
dc.subjectCardiomyocytespt_PT
dc.subjectCardiotoxicitypt_PT
dc.subjectMetabolismpt_PT
dc.titleMetabolism is required for the expression of ecstasy-induced cardiotoxicity in vitropt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage632pt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPage623pt_PT
oaire.citation.titleChemical Research in Toxicologypt_PT
oaire.citation.volume17pt_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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