title: Synthesis and cytotoxic profile of 3,4-methylenedioxymethamphetamine ("ecstasy") and its metabolites on undifferentiated PC12 cells: A putative structure-toxicity relationship.
abstract: The toxicological and redox profiles of MDMA and its major metabolites (MDA, alpha-methyldopamine, N-methyl-alpha-methyldopamine, 6-hydroxy-alpha-methyldopamine, 3-methoxy-alpha-methyldopamine) were studied to establish a structure-toxicity relationship and determine their individual contribution to cell death induction by apoptosis and/or necrosis. The results of the comparative toxicity study, using undifferentiated PC12 cells, strongly suggest that the metabolites possessing a catecholic group are more toxic to the cells than MDMA and metabolites with at least one protected phenolic group. Redox studies reveal that an oxidative mechanism seems to play an important role in metabolite cytotoxicity. Nuclear features of apoptosis and/or necrosis show that most of the metabolites, particularly N-methyl-alpha-methyldopamine, induce cell death by apoptosis, largely accompanied by necrotic features. No significant differences were found between MDMA and the metabolites, concerning overall characteristics of cell death. These results may be useful to ascertain the contribution of metabolism in MDMA neurotoxicity molecular mechanisms.
authors.affiliation: CEQOFFUP, Faculdade de Farmácia, Universidade do Porto, 4050-047 Porto, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Milhazes
authors.forename: Teresa
authors.initials: T
authors.lastname: Cunha-Oliveira
authors.forename: Pedro
authors.initials: P
authors.lastname: Martins
authors.forename: Jorge
authors.initials: J
authors.lastname: Garrido
authors.forename: Catarina
authors.initials: C
authors.lastname: Oliveira
authors.forename: A Cristina
authors.initials: AC
authors.lastname: Rego
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000235:genetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D016716:PC12 Cells; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002843:Chromatin; D015104:3,4-Methylenedioxyamphetamine