Neurotoxic thioether adducts of 3,4-methylenedioxymethamphetamine identified in human urine after ecstasy ingestion

Ximena Perfetti, Brian O'Mathúna, Nieves Pizarro, Elisabet Cuyàs, Olha Khymenets, Bruno Almeida, Manuela Pellegrini, Simona Pichini, Serrine S. Lau, Terrence J. Monks, Magí Farré, Jose Antonio Pascual, Jesús Joglar, Rafael De La Torre

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1448-1455
Number of pages8
JournalDrug Metabolism and Disposition
Volume37
Issue number7
DOIs
StatePublished - Jul 1 2009

    Fingerprint

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Perfetti, X., O'Mathúna, B., Pizarro, N., Cuyàs, E., Khymenets, O., Almeida, B., Pellegrini, M., Pichini, S., Lau, S. S., Monks, T. J., Farré, M., Pascual, J. A., Joglar, J., & De La Torre, R. (2009). Neurotoxic thioether adducts of 3,4-methylenedioxymethamphetamine identified in human urine after ecstasy ingestion. Drug Metabolism and Disposition, 37(7), 1448-1455. https://doi.org/10.1124/dmd.108.026393