Metabolism Is Required for the Expression of Ecstasy-Induced Cardiotoxicity in Vitro
Márcia Carvalho, Fernando Remião, Nuno Milhazes, Fernanda Borges, Eduarda Fernandes, Maria Do Céu Monteiro, Maria José Gonçalves, Vítor Seabra, Francisco Amado, Félix Carvalho, Maria de Lourdes Bastos
Chemical Research in Toxicology April 27, 2004 DOI: 10.1021/tx049960f (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Freshly isolated adult rat cardiomyocytes |
| Interventions | MDMA MDA N-Me-alpha-MeDA alpha-MeDA |
| Dose | 0.1, 0.2, 0.4, 0.8, and 1.6 mM |
| Duration | 4 hours |
| Topics | MDMA |
| Keywords | Glutathione reductase Pharmacology Toxicity In vitro Intracellular Glutathione disulfide Biochemistry Glutathione peroxidase |
| Citations | 77 |
| Key points | MDMA and MDA were not directly toxic to rat cardiomyocytes, but their catechol metabolites N-Me-alpha-MeDA and alpha-MeDA caused significant toxicity, with N-Me-alpha-MeDA being the most toxic. |
Abstract
Cardiovascular complications associated with 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse have increasingly been reported. The indirect effect of MDMA mediated by a sustained high level of circulating biogenic amines may contribute to the cardiotoxic effects, but other factors, like the direct toxic effects of MDMA and its metabolites in cardiac cells, remain to be investigated. Thus, the objective of the present in vitro study was to evaluate the potential cardiotoxic effects of MDMA and its major metabolites 3,4-methylenedioxyamphetamine (MDA), N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA), and alpha-methyldopamine (alpha-MeDA) using freshly isolated adult rat cardiomyocytes. The cell suspensions were incubated with these compounds in the final concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 mM for 4 h. alpha-MeDA, N-Me-alpha-MeDA, and their respective aminochromes (oxidation products) were quantified in cell suspensions by HPLC-DAD. The toxic effects were evaluated at hourly intervals for 4 h by measuring the percentage of cells with normal morphology, glutathione (GSH), and glutathione disulfide (GSSG); intracellular Ca(2+), ATP, and ADP; and the cellular activities of glutathione peroxidase, glutathione reductase, and glutathione-S-transferase. No toxic effects were found after exposure of rat cardiomyocytes to MDMA or MDA at any of the tested concentrations for 4 h. In contrast, their catechol metabolites N-Me-alpha-MeDA and alpha-MeDA induced significant toxicity in rat cardiomyocytes. The toxic effects were characterized by a loss of normal cell morphology, which was preceded by a loss of GSH homeostasis due to conjugation of GSH with N-Me-alpha-MeDA and alpha-MeDA, sustained increase of intracellular Ca(2+) levels, ATP depletion, and decreases in the antioxidant enzyme activities. The oxidation of N-Me-alpha-MeDA and alpha-MeDA into the toxic compounds N-methyl-alpha-methyldopaminochrome and alpha-methyldopaminochrome, respectively, was also verified in cell suspensions incubated with these MDMA metabolites. The results obtained in this study provide evidence that the metabolism of MDMA into N-Me-alpha-MeDA and alpha-MeDA is required for the expression of MDMA-induced cardiotoxicity in vitro, being N-Me-alpha-MeDA the most toxic of the studied metabolites.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 26
- Mechanisms of MDMA (Ecstasy)-Induced Oxidative Stress, Mitochondrial Dysfunction, and Organ Damage Current Pharmaceutical Biotechnology June 27, 2010
- Pro‐oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes British Journal of Pharmacology April 21, 2011
- Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions Critical Reviews in Toxicology October 3, 2012
- Cardiac effects of MDMA on the metabolic profile determined with 1H‐magnetic resonance spectroscopy in the rat NMR in Biomedicine November 4, 2008
- Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites JOURNAL OF HEALTH SCIENCE 2007
and 21 more in the library
Cites 10
- Pathology of deaths associated with "ecstasy" and "eve" misuse. Journal of Clinical Pathology February 1, 1996
- Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity Chemical Research in Toxicology November 19, 1999
- Effects of Intracerebroventricular Administration of 5-(Glutathion-S-yl)-α-methyldopamine on Brain Dopamine, Serotonin, and Norepinephrine Concentrations in Male Sprague-Dawley Rats Chemical Research in Toxicology 1996
- Serotonergic Neurotoxicity of 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylendioxymethamphetamine (Ecstasy) Is Potentiated by Inhibition of γ-Glutamyl Transpeptidase Chemical Research in Toxicology May 31, 2001
- Hepatotoxicity of 3,4-methylenedioxyamphetamine and alpha-methyldopamine in isolated rat hepatocytes: formation of glutathione conjugates. Archives of Toxicology January 2004
and 5 more in the library