Métabolites de l'ecstasy et phénomènes de cytotoxicité

Intracerebroventricular injection of methylenedioxymethamphetamine (MDMA, ecstasy) in rats fails to reproduce long-term toxic effects observed after peripheral administration. Therefore, systemic metabolites would play an essential role in the development of cytotoxicity. In humans, the major metabolite is the 3,4-dihydroxymethamphetamine derivative (HHMA), which is easily oxidizable to the orthoquinone species. This can either participate to redox cycling generating semiquinone radicals and reactive oxygen species (ROS), or react with endogenous thiol derivatives yielding catechol-thioether conjugates whose the toxicity is not well established. A one pot electrochemical procedure has been developed allowing the synthesis of several catechol-thioether metabolites. Two in vitro assays have been used for evaluating their specific cytotoxicity. The first one is a bacterial assay, which shows that HHMA and some catechol-thioether conjugates can induce toxic phenomena leading to the formation of ROS, through redox cycling processes involving o-quinonoid species. The second one is an assay of cellular viability, performed on rat hippocampal pyramidal neurons. It confirms that some of these metabolites exhibit a noticeable cytotoxicity by markedly eliciting both necrosis and apoptosis markers.