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Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy Ingestion

Human Pharmacology and Clinical Neurosciences Research Group (X.P., B.O., N.P., E.C., O.K., B.A., M.F., R.d.T.) and Bioanalysis and Analytical Services Research Group (J.A.P.), Institut Municipal d'Investigació Mèdica-Hospital del Mar, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain (X.P., B.O., O.K., B.A., R.T.); Research Unit on Biotransformations and BioActive Molecules, Catalonia Institute for Advanced Chemistry, Spanish Council for Scientific Research, Barcelona, Spain (B.A., J.J.); Universidad Autónoma de Barcelona, Barcelona, Spain (E.C., M.F.); Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona Health Sciences Center, Tucson, Arizona (S.S.L., T.J.M.); and Department of Therapeutic Research and Medicines Evaluation, Instituto Superiore di Sanita, Rome, Italy (M.P., S.P.)

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.

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