Synthesis and cytotoxic profile of 3,4-methylenedioxymethamphetamine ("ecstasy") and its metabolites on undifferentiated PC12 cells: A putative structure-toxicity relationship.
Nuno Milhazes, Teresa Cunha-Oliveira, Pedro Martins, Jorge Garrido, Catarina Oliveira, A Cristina Rego, Fernanda Borges
Chemical Research in Toxicology October 2006 DOI: 10.1021/tx060123i (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro comparative toxicology study Peer reviewed |
|---|---|
| Population | Undifferentiated PC12 cells |
| Interventions | MDMA MDA alpha-methyldopamine N-methyl-alpha-methyldopamine 6-hydroxy-alpha-methyldopamine 3-methoxy-alpha-methyldopamine |
| Topics | MDMA |
| Key points | Metabolites with a catechol group were more toxic to PC12 cells than MDMA and metabolites with at least one protected phenolic group, and oxidative mechanisms appeared important in this cytotoxicity. Most metabolites, particularly N-methyl-alpha-methyldopamine, induced cell death mainly by apoptosis with necrotic features, while overall cell-death characteristics did not differ significantly between MDMA and its metabolites. |
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- Mechanisms of MDMA (Ecstasy)-Induced Oxidative Stress, Mitochondrial Dysfunction, and Organ Damage Current Pharmaceutical Biotechnology June 27, 2010
- Mechanism of 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy)‐mediated mitochondrial dysfunction in rat liver PROTEOMICS September 1, 2008
- Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions Critical Reviews in Toxicology October 3, 2012
- Comparative potencies of 3,4‐methylenedioxymethamphetamine (MDMA) analogues as inhibitors of [3H]noradrenaline and [3H]5‐HT transport in mammalian cell lines British Journal of Pharmacology September 24, 2007
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Cites 23
- Hallucinogenic Amphetamine Selectively Destroys Brain Serotonin Nerve Terminals Science September 6, 1985
- (±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals Neuropsychobiology 2000
- The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype British Journal of Pharmacology August 1, 1995
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
- A study of the mechanisms involved in the neurotoxic action of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain British Journal of Pharmacology December 1, 2001
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