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Synthesis and Cytotoxic Profile of 3,4-Methylenedioxymethamphetamine (“Ecstasy”) and Its Metabolites on Undifferentiated PC12 Cells:  A Putative Structure−Toxicity Relationship

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CEQOFFUP, Faculdade de Farmácia, Universidade do Porto, 4050-047 Porto, Portugal, Instituto Superior Ciências da Saúde-Norte, 4585-116 Gandra, PRD, Portugal, Instituto de Bioquímica, Faculdade de Medicina e Centro de Neurociências e Biologia Celular de Coimbra, Universidade de Coimbra, 3004-504 Coimbra, Portugal, Departamento de Química Orgânica, Faculdade de Farmácia, Universidade do Porto, 4050-047 Porto, Portugal, Unidade I&D “Química-Física Molecular”, and Departamento de Engenharia Química, Instituto Superior de Engenharia do Porto, IPP, Porto, Portugal
Cite this: Chem. Res. Toxicol. 2006, 19, 10, 1294–1304
Publication Date (Web):September 7, 2006
https://doi.org/10.1021/tx060123i
Copyright © 2006 American Chemical Society
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Abstract

Abstract Image

The toxicological and redox profiles of MDMA and its major metabolites (MDA, α-methyldopamine, N-methyl-α-methyldopamine, 6-hydroxy-α-methyldopamine, 3-methoxy-α-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-α-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.

†

 CEQOFFUP, Universidade do Porto.

‡

 Instituto Superior Ciências da Saúde - Norte.

§

 Universidade de Coimbra.

‖

 Departamento de Química Orgânica, Universidade do Porto.

⊥

 Unidade I&D “Química-Física Molecular”.

#

 Instituto Superior de Engenharia do Porto.

*

 Corresponding author. Tel:  +351222078900. Fax:  +351222003977. E-mail:  [email protected]

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