title: Thioether metabolites of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine inhibit human serotonin transporter (hSERT) function and simultaneously stimulate dopamine uptake into hSERT-expressing SK-N-MC cells.
abstract: 3,4-Methylenedioxyamphetamine (MDA) and 3,4-methyl-enedioxymethamphetamine (MDMA, ecstasy) are widely abused amphetamine derivatives that target the serotonin system. The serotonergic neurotoxicity of MDA and MDMA seems dependent on their systemic metabolism. 5-(Glutathion-S-yl)-alpha-methyldopamine [5-(GSyl)-alpha-MeDA] and 2,5-bis(glutathion-S-yl)-alpha-methyldopamine [2,5-bis(GSyl)-alpha-MeDA], metabolites of MDA and MDMA, are also selective serotonergic neurotoxicants and produce behavioral and neurochemical changes similar to those seen with MDA and MDMA. We now show that 5-(GSyl)-alpha-MeDA and 2,5-bis(GSyl)-alpha-MeDA are more potent than MDA and MDMA (K(i) = 69, 50, 107, and 102 microM, respectively) at inhibiting 5-hy-droxytryptamine (serotonin) transport into SK-N-MC cells transiently transfected with the human serotonin transporter (hSERT). Moreover, 5-(GSyl)-alpha-MeDA and 2,5-bis(GSyl)-alpha-MeDA simultaneously stimulated dopamine (DA) transport into the hSERT-expressing cells, an effect attenuated by fluoxetine, indicating that stimulated DA transport was hSERT-dependent. Finally, 5-(GSyl)-alpha-MeDA and 2,5-bis(GSyl)-alpha-MeDA, and to a lesser extent MDA and MDMA, induced a concentration and time-dependent increase in reactive oxygen species (ROS) in both hSERT and human dopamine transporter-transfected cells. Fluoxetine attenuated the increase in ROS generation in hSERT-expressing cells. The results are consistent with the view that the serotonergic neurotoxicity of MDA and MDMA may be mediated by the metabolism-dependent stimulation of DA transport into hSERT-expressing cells and ROS generation by redox active catechol-thioether metabolites and DA.
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Jones
authors.forename: Serrine S
authors.initials: SS
authors.lastname: Lau
authors.forename: Terrence J
authors.initials: TJ
authors.lastname: Monks
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; C493230:SLC6A4 protein, human; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine