title: Inhibition potential of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites on the in vitro monoamine oxidase (MAO)-catalyzed deamination of the neurotransmitters serotonin and dopamine.
abstract: Neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA) is still controversially discussed. Formation of reactive oxygen species e.g. based on elevated dopamine (DA) concentrations and DA quinone formation is discussed among others. Inhibition potential of MDMA metabolites regarding neurotransmitter degradation by catechol-O-methyltransferase and sulfotransferase was described previously. Their influence on monoamine oxidase (MAO) - the major DA degradation pathway-has not yet been studied in humans. Therefore the inhibition potential of MDMA and its metabolites on the deamination of the neurotransmitters DA and serotonin (5-HT) by MAO-A and B using recombinant human enzymes in vitro should be investigated. In initial studies, MDMA and MDA showed relevant inhibition (>30%) toward MAO A for 5-HT and DA. No relevant effects toward MAO B were observed. Further investigation on MAO-A revealed MDMA as a competitive inhibitor of 5-HT and DA deamination with Ki 24.5±7.1 μM and 18.6±4.3 μM respectively and MDA as a mixed-type inhibitor with Ki 7.8±2.6 μM and 8.4±3.2 μM respectively. Although prediction of in vivo relevance needs to be done with care, relevant inhibitory effects at expected plasma concentrations after recreational MDMA consumption seems unlikely based on the obtained data.
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Institute of Forensic Medicine, University of Zurich, Switzerland. Electronic address: andrea.steuer@irm.uzh.ch.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Steuer
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Institute of Forensic Medicine, University of Zurich, Switzerland.
authors.forename: Martina I
authors.initials: MI
authors.lastname: Boxler
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Institute of Forensic Medicine, University of Zurich, Switzerland.
authors.forename: Lorena
authors.initials: L
authors.lastname: Stock
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Institute of Forensic Medicine, University of Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kraemer
mesh_terms: D002394:Catechol O-Methyltransferase / Q000378:metabolism; D002853:Chromatography, Liquid; D003641:Deamination; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000097:blood / Q000633:toxicity*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000097:blood / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000378:metabolism; D017382:Reactive Oxygen Species; D012701:Serotonin / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D008996:Monoamine Oxidase Inhibitors; D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D012701:Serotonin; C104705:dopamine quinone; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine
keywords: In vitro; Inhibition; MAO; MDMA; Neurotransmitter