Role of metabolites in MDMA (ecstasy)-induced nephrotoxicity: an in vitro study using rat and human renal proximal tubular cells.
Márcia Carvalho, Gabrielle Hawksworth, Nuno Milhazes, Fernanda Borges, Terrence J. Monks, Eduarda Fernandes, Félix Carvalho, Maria Lourdes Bastos
Archives of Toxicology October 2002 DOI: 10.1007/s00204-002-0381-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro cell culture study Peer reviewed |
|---|---|
| Population | Primary cultures of rat and human renal proximal tubular cells (PTCs) |
| Interventions | MDMA MDA alpha-methyldopamine (alpha-MeDA) 5-(glutathion-S-yl)-alpha-MeDA 2 5-bis(glutathion-S-yl)-alpha-MeDA acivicin bestatin |
| Dose | 100-800 microM MDMA and MDA; 800 microM alpha-MeDA; 400 microM 5-(glutathion-S-yl)-alpha-MeDA and 2,5-bis(glutathion-S-yl)-alpha-MeDA |
| Measures | mitochondrial MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay |
| Topics | MDMA |
| Key points | MDMA and MDA were not toxic to rat or human renal proximal tubular cells up to 800 microM, whereas the metabolite alpha-MeDA and especially its glutathione conjugates caused substantial cell death (e.g., 400 microM 5-(glutathion-S-yl)-alpha-MeDA killed about 80% of rat and 70% of human cells). The authors argue that metabolism is required for MDMA-induced renal toxicity in vitro and that detoxication of the conjugate involves gamma-GT and aminopeptidase M. |
Abstract
The metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has recently been implicated in the mechanisms underlying ecstasy-induced neurotoxicity and hepatotoxicity. However, its potential role in ecstasy-induced kidney toxicity has yet to be investigated. Thus, primary cultures of rat and human renal proximal tubular cells (PTCs) were used to investigate the cytotoxicity induced by MDMA and its metabolites methylenedioxyamphetamine (MDA), alpha-methyldopamine (alpha-MeDA), and the glutathione (GSH) conjugates 5-(glutathion- S-yl)-alpha-MeDA and 2,5- bis(glutathion- S-yl)-alpha-MeDA. Cell viability was evaluated using the mitochondrial MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. MDMA and MDA were not found to be toxic to either rat or human PTCs at any concentration tested (100-800 micro M). In contrast, 800 micro M alpha-MeDA caused 60% and 40% cell death in rat and human PTCs, respectively. Conjugation of alpha-MeDA with GSH resulted in the formation of even more potent nephrotoxicants. Thus, exposure of rat and human PTC monolayers to 400 micro M 5-(glutathion- S-yl)-alpha-MeDA caused approximately 80% and 70% cell death, respectively. 5-(Glutathion- S-yl)-alpha-MeDA (400 micro M) was more toxic than 2,5- bis(glutathion- S-yl)-alpha-MeDA to rat renal PTCs but equally potent in human renal PTCs. Pre-incubation of rat PTCs with either acivicin, an inhibitor of gamma-glutamyl transpeptidase (gamma-GT), or bestatin, an inhibitor of aminopeptidase M, resulted in increased toxicity of 5-(glutathion- S-yl)-alpha-MeDA but had no effect on 2,5- bis(glutathion- S-yl)-alpha-MeDA-mediated cytotoxicity. The present data provide evidence that metabolism is required for the expression of MDMA-induced renal toxicity in vitro. In addition, metabolism of 5-(glutathion- S-yl)-alpha-MeDA by gamma-GT and aminopeptidase M to the corresponding cystein- S-yl-glycine and/or cystein- S-yl conjugates is likely to be associated with detoxication of this compound. Thus, it appears that toxicity induced by thioether metabolites of ecstasy at the apical membrane of renal proximal tubular cells is the result of extracellular events, presumably redox cycling.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 21
- Metabolism Is Required for the Expression of Ecstasy-Induced Cardiotoxicity in Vitro Chemical Research in Toxicology April 27, 2004
- 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
- Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites JOURNAL OF HEALTH SCIENCE 2007
- Time-Dependent Molecular Changes Following MDMA-Induced Nephrotoxicity. Iranian journal of pharmaceutical research : IJPR 2024
and 16 more in the library
Cites 9
- Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity Chemical Research in Toxicology November 19, 1999
- Fatal multi-organ failure after suicidal overdose with MDMA, `Ecstasy': case report and review of the literature Human & Experimental Toxicology February 1, 1999
- 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
- Acute renal failure due to accelerated hypertension following ingestion of 3,4-methylenedioxymethamphetamine (‘ecstasy’) Nephrology, Dialysis, Transplantation March 1, 1995
- Identification of the human cytochromes P450 involved in the oxidative metabolism of "Ecstasy"-related designer drugs. Biochemical Pharmacology June 15, 2000
and 4 more in the library