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Hepatotoxicity of 3,4-methylenedioxyamphetamine and α-methyldopamine in isolated rat hepatocytes: formation of glutathione conjugates

2004Journal article Restricted access
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dc.contributor.authorBastos, Maria de Lourdes
dc.contributor.authorCarvalho, Márcia
dc.contributor.authorMilhazes, Nuno
dc.contributor.authorRemião, Fernando
dc.contributor.authorBorges, Fernanda
dc.contributor.authorFernandes, Eduarda
dc.contributor.authorAmado, Francisco
dc.contributor.authorMonks, Terrence J.
dc.contributor.authorCarvalho, Félix
dc.date.accessioned2021-06-30T15:13:07Z
dc.date.available2021-06-30T15:13:07Z
dc.date.issued2004
dc.description.abstractThe amphetamine designer drugs 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and its N-demethylated analogue 3,4-methylenedioxyamphetamine (MDA or "love") have been extensively used as recreational drugs of abuse. MDA itself is a main MDMA metabolite. MDMA abuse in humans has been associated with numerous reports of hepatocellular damage. Although MDMA undergoes extensive hepatic metabolism, the role of metabolites in MDMA-induced hepatotoxicity remains unclear. Thus, the aim of the present study was to evaluate the effects of MDA and alpha-methyldopamine (alpha-MeDA), a major metabolite of MDA, in freshly isolated rat hepatocyte suspensions. The cells were incubated with MDA or alpha-MeDA at final concentrations of 0.1, 0.2, 0.4, 0.8, or 1.6 mM for 3 h. The toxic effects induced following incubation of hepatocyte suspensions with these metabolites were evaluated by measuring cell viability, the extent of lipid peroxidation, levels of glutathione (GSH) and glutathione disulfide (GSSG), the formation of GSH conjugates, and the activities of GSSG reductase (GR), GSH peroxidase (GPX), and GSH S-transferase (GST). MDA induced a concentration- and time-dependent GSH depletion, but had a negligible effect on lipid peroxidation, cell viability, or on the activities of GR, GPX, and GST. In contrast, alpha-MeDA (1.6 mM, 3 h) induced a marked depletion of GSH accompanied by a loss on cell viability, and decreases in GR, GPX and GST activities, although no significant effect on lipid peroxidation was found. For both metabolites, GSH depletion was not accompanied by increases in GSSG levels; rather, 2-(glutathion- S-yl)-alpha-MeDA and 5-(glutathion- S-yl)-alpha-MeDA were identified by HPLC-DAD/EC within cells incubated with MDA or alpha-MeDA. The results provide evidence that one of the early consequences of MDMA metabolism is a disruption of thiol homeostasis, which may result in loss of protein function and the initiation of a cascade of events leading to cellular damage.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1007/s00204-003-0510-7pt_PT
dc.identifier.eissn1432-0738
dc.identifier.issn0340-5761
dc.identifier.urihttp://hdl.handle.net/10284/9990
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relationThis work was supported by PhD grants from Fundação para a Ciência e Tecnologia (Praxis XXI/BD/20087/99 and Praxis XXI/BD/18520/98) and Programa Operacional Ciência, Tecnologia e Inovação (POCTI), Portugal, in co-participation with Fonds Européen de Développement Régional (FEDER) (project POCTI/36099/FCB/2000). The experiments are declared to comply with the current laws of Portugal.pt_PT
dc.subject3,4-Methylenedioxyamphetaminept_PT
dc.subjecta-Methyldopaminept_PT
dc.subjectRat hepatocytespt_PT
dc.subjectGlutathione conjugatespt_PT
dc.titleHepatotoxicity of 3,4-methylenedioxyamphetamine and α-methyldopamine in isolated rat hepatocytes: formation of glutathione conjugatespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage24pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage16pt_PT
oaire.citation.titleArchives of Toxicologypt_PT
oaire.citation.volume78pt_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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