Synthesis and cytotoxic profile of 3,4-methylenedioxymethamphetamine ("ecstasy") and its metabolites on undifferentiated PC12 cells: A putative structure-toxicity relationship

Chemical Research in Toxicology
Nuno MilhazesFernanda Borges

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.

Citations

Mar 13, 2010·Organic Letters·Akop YepremyanThomas G Minehan
May 12, 2011·Chemical Research in Toxicology·Anne NeudörfferMartine Largeron
Nov 11, 2014·International Journal of Medicinal Chemistry·Suvarna ShenviG Chandrasekara Reddy
Dec 14, 2011·The Veterinary Quarterly·Irene Antolino-LoboMajorie B M van Duursen
Dec 1, 2012·Toxicology Letters·Patrícia Silva FerreiraJoão Paulo Capela
Apr 29, 2008·Brain Research Reviews·Teresa Cunha-OliveiraCatarina R Oliveira
Feb 19, 2008·Brain, Behavior, and Immunity·Daniel A NelsonKenneth L Bost
Nov 12, 2013·Toxicology in Vitro : an International Journal Published in Association with BIBRA·C DowneyK M O'Boyle
Apr 15, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Irene Antolino-LoboMajorie B M van Duursen
Nov 7, 2017·Toxicology Mechanisms and Methods·Fahimeh MobarakiAlireza Ebrahimzadeh-Bideskan
Aug 19, 2009·The Journal of Physical Chemistry. a·E Manuela GarridoFernanda Borges
Dec 13, 2007·Chemical Reviews·Anniina ErkkiläPetri M Pihko
Jul 8, 2017·Neuroscience Letters·Susan M LantzSyed F Ali

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis