Abstract
3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely misused synthetic amphetamine derivative and a serotonergic neurotoxicant in animal models and possibly humans. The underlying mechanism of neurotoxicity involves the formation of reactive oxygen species although their source remains unclear. It has been postulated that MDMA-induced neurotoxicity is mediated via the formation of bioreactive metabolites. In particular, the primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), subsequently cause the formation of glutathione and N-acetylcysteine conjugates, which retain the ability to redox cycle and are serotonergic neurotoxicants in rats. Although the presence of such metabolites has been recently demonstrated in rat brain microdialysate, their formation in humans has not been reported. The present study describes the detection of 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine (N-Ac-5-Cys-HHMA) and 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine (N-Ac-5-Cys-HHA) in human urine of 15 recreational users of MDMA (1.5 mg/kg) in a controlled setting. The results reveal that in the first 4 h after MDMA ingestion ∼0.002% of the administered dose was recovered as thioether adducts. Genetic polymorphisms in CYP2D6 and catechol-O-methyltransferase expression, the combination of which are major determinants of steady-state levels of HHMA and 4-hydroxy-3-methoxyamphetamine, probably explain the interindividual variability seen in the recovery of N-Ac-5-Cys-HHMA and N-Ac-5-Cys-HHA. In summary, the formation of neurotoxic thioether adducts of MDMA has been demonstrated for the first time in humans. The findings lend weight to the hypothesis that the bioactivation of MDMA to neurotoxic metabolites is a relevant pathway to neurotoxicity in humans.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute on Drug Abuse [Grant 1R0-1DA017987-10A2]; a postdoctoral grant by the Secretaria de Estado de Universidades e Investigación del Ministerio de Educación y Ciencia, Spain (to N.P.); a de Gestió d'Ajuts Universitaris i de Recerca predoctoral fellowship Generalitat de Catalunya, Spain (to X.P.); Ministerio de Educación y Ciencia (Spain) [Grant SAF2005-0189]; and Generalitat de Catalunya (Spain) [Grant 2005SGR00032]. We acknowledge assistance from the National Institute of Environmental Health Sciences-supported Southwest Environmental Health Sciences Center [Grant P30-ES06694] at the University of Arizona.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.026393.
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ABBREVIATIONS: MDMA, 3,4-methylenedioxymethamphetamine; 5-HT, serotonin, 5-hydroxytryptamine; MDA, 3,4-methylenedioxyamphetamine; HHMA, 3,4-dihydroxymethamphetamine or N-methyl-α-methyldopamine; HHA, 3,4-dihydroxyamphetamine or α-methyldopamine; GSH, glutathione; NAC, N-acetylcysteine; HMA, 4-hydroxy-3-methoxy-amphetamine; COMT, catechol-O-methyltransferase; HPLC, high-performance liquid chromatography; DTT, dithiothreitol; PBA, phenylboronic acid; N-Ac-5-Cys-HHMA, 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine; N-Ac-5-Cys-HHA, 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine; N-Ac-5-Cys-O-Me-HHMA, 5-(N-acetylcystein-S-yl)-methylesther-3,4-dihydroxymethamphetamine; IS, internal standard; MS/MS, tandem mass spectrometry; QC, quality control; TFA, trifluoroacetic acid; LC, liquid chromatography; MS, mass spectrometry; MRM, multiple reaction monitoring; HMMA, 4-hydroxy-3-methoxymethamphetamine.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material. - Accepted April 2, 2009.
- Received January 7, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy Ingestion
