RT Journal Article
SR Electronic
T1 Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy Ingestion
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1448
OP 1455
DO 10.1124/dmd.108.026393
VO 37
IS 7
A1 Perfetti, Ximena
A1 O'Mathúna, Brian
A1 Pizarro, Nieves
A1 Cuyàs, Elisabet
A1 Khymenets, Olha
A1 Almeida, Bruno
A1 Pellegrini, Manuela
A1 Pichini, Simona
A1 Lau, Serrine S.
A1 Monks, Terrence J.
A1 Farré, Magí
A1 Pascual, Jose Antonio
A1 Joglar, Jesús
A1 de la Torre, Rafael
YR 2009
UL http://dmd.aspetjournals.org/content/37/7/1448.abstract
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.