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

摘要: 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely misused synthetic amphetamine derivative and serotonergic neurotoxicant in animal models possibly humans. The underlying mechanism of neurotoxicity involves the formation reactive oxygen species although their source remains unclear. It has been postulated that MDMA-induced mediated via bioreactive metabolites. In particular, primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) 3,4-dihydroxyamphetamine (HHA), subsequently cause glutathione N-acetylcysteine conjugates, which retain ability to redox cycle are neurotoxicants rats. Although presence such metabolites recently demonstrated rat brain microdialysate, humans not reported. present study describes detection 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine (N-Ac-5-Cys-HHMA) 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine (N-Ac-5-Cys-HHA) human urine 15 recreational users MDMA (1.5 mg/kg) controlled setting. results reveal first 4 h after ingestion ∼0.002% administered dose was recovered as thioether adducts. Genetic polymorphisms CYP2D6 catechol-O-methyltransferase expression, combination major determinants steady-state levels HHMA 4-hydroxy-3-methoxyamphetamine, probably explain interindividual variability seen recovery N-Ac-5-Cys-HHMA N-Ac-5-Cys-HHA. summary, neurotoxic adducts for time findings lend weight hypothesis bioactivation relevant pathway