PT  - JOURNAL ARTICLE
AU  - Ximena Perfetti
AU  - Brian O'Mathúna
AU  - Nieves Pizarro
AU  - Elisabet Cuyàs
AU  - Olha Khymenets
AU  - Bruno Almeida
AU  - Manuela Pellegrini
AU  - Simona Pichini
AU  - Serrine S. Lau
AU  - Terrence J. Monks
AU  - Magí Farré
AU  - Jose Antonio Pascual
AU  - Jesús Joglar
AU  - Rafael de la Torre
TI  - Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy Ingestion
AID  - 10.1124/dmd.108.026393
DP  - 2009 Jul 01
TA  - Drug Metabolism and Disposition
PG  - 1448--1455
VI  - 37
IP  - 7
4099  - http://dmd.aspetjournals.org/content/37/7/1448.short
4100  - http://dmd.aspetjournals.org/content/37/7/1448.full
SO  - Drug Metab Dispos2009 Jul 01; 37
AB  - 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.