title: Inhibition of 3,4-methylenedioxymethamphetamine metabolism leads to marked decrease in 3,4-dihydroxymethamphetamine formation but no change in serotonin neurotoxicity: implications for mechanisms of neurotoxicity.
abstract: 3,4-Methylenedioxymethamphetamine (MDMA)'s O-demethylenated metabolite, 3,4-dihydroxymethamphetamine (HHMA), has been hypothesized to serve as a precursor for the formation of toxic catechol-thioether metabolites (e.g., 5-N-acetylcystein-S-yl-HHMA) that mediate MDMA neurotoxicity. To further test this hypothesis, HHMA formation was blocked with dextromethorphan (DXM), which competitively inhibits cytochrome P450 enzyme-mediated O-demethylenation of MDMA to HHMA. In particular, rats were randomly assigned to one of four treatment groups (n = 9-12 per group): (1) Saline/MDMA; (2) DXM/MDMA; (3) DXM/Saline; (4) Saline/Saline. During drug exposure, time-concentration profiles of MDMA and its metabolites were determined, along with body temperature. One week later, brain serotonin (5-HT) neuronal markers were measured in the same animals. DXM did not significantly alter core temperature in MDMA-treated animals. A large (greater than 70%) decrease in HHMA formation had no effect on the magnitude of MDMA neurotoxicity. These results cast doubt on the role of HHMA-derived catechol-thioether metabolites in the mechanism of MDMA neurotoxicity.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore 21224, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Mueller
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.forename: Concepcion
authors.initials: C
authors.lastname: Maldonado Adrian
authors.forename: Una D
authors.initials: UD
authors.lastname: McCann
authors.forename: George A
authors.initials: GA
authors.lastname: Ricaurte
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003846:Deoxyepinephrine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000633:toxicity; D003915:Dextromethorphan / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism / Q000633:toxicity*; D013440:Sulfides / Q000737:chemistry / Q000378:metabolism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D013440:Sulfides; C069512:alpha-methylepinine; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; C051800:3,4-methylenedioxyethamphetamine; D003846:Deoxyepinephrine