Chemical Research in Toxicology
November 1, 1988
H. K. Lim, R. L. Foltz
117 citations
Four metabolic pathways of MDMA in rats have been identified: N-demethylation, O-dealkylation, deamination, and conjugation (O-methylation, O-glucuronidation, or O-sulfation). Specific metabolites include 3-hydroxy-4-methoxymethamphetamine, 4-hydroxy-3-methoxymethamphetamine, 3,4-dihydroxymethamphetamine, 4-hydroxy-3-methoxyamphetamine, MDA, and several phenylacetone derivatives. Most metabolites were excreted in urine as glucuronide or sulfate conjugates, with traces of free forms present. N-Demethyl and 3-O-methyl metabolites appeared in brain, liver, blood, and feces. Liver and brain supernatants metabolized MDMA to several of these compounds.
Chemical Research in Toxicology
November 19, 1999
Fengju Bai, Serrine S. Lau, Terrence J. Monks
109 citations
Injecting MDMA or MDA directly into the brain does not cause the serotonin nerve damage seen when these drugs are given peripherally, indicating that a toxic metabolite is responsible. A major metabolite, alpha-methyldopamine (alpha-MeDA), forms thioether conjugates with glutathione or N-acetylcysteine. When injected directly into the striatum or cortex of rats, certain conjugates—5-(glutathion-S-yl)-alpha-MeDA, 5-(N-acetylcystein-S-yl)-alpha-MeDA, and 2,5-bis(glutathion-S-yl)-alpha-MeDA—significantly reduced serotonin concentrations in those regions seven days later, without affecting dopamine or norepinephrine levels. The damage was limited to serotonin nerve terminals, sparing cell body regions. These conjugates are selective serotonergic neurotoxicants, but whether they cause the toxicity seen after systemic MDMA or MDA administration remains unproven.
Chemical Research in Toxicology
August 2, 2001
Mireia Segura, Jordi Ortuño, Magı́ Farré et al.
105 citations
A new method using strong cation-exchange solid-phase extraction and high-performance liquid chromatography with electrochemical detection was validated for measuring the metabolite 3,4-dihydroxymethamphetamine (HHMA) in plasma and urine. Applied to samples from healthy volunteers given MDMA (ecstasy), HHMA appeared as a major metabolite, with peak plasma concentrations (154.5 microg/L) and overall exposure (AUC 1990.9 microg/L h) similar to those of MDMA itself. Urinary recovery of HHMA over 24 hours accounted for 17.7% of the 100 mg MDMA dose, raising total recovery of MDMA and its metabolites to 58%. The method is accurate and precise for pharmacokinetic studies, and measuring HHMA may help clarify its role in MDMA metabolism and potential neurotoxicity.
Chemical Research in Toxicology
April 27, 2004
Márcia Carvalho, Fernando Remião, Nuno Milhazes et al.
77 citations
MDMA (ecstasy) and its major metabolite MDA did not directly damage heart cells from adult rats in the lab, but two further metabolites, N-Me-alpha-MeDA and alpha-MeDA, caused significant toxicity. These catechol metabolites triggered a loss of normal cell shape, depletion of the antioxidant glutathione, sustained increases in intracellular calcium, drops in ATP, and reduced activity of antioxidant enzymes. N-Me-alpha-MeDA was the most toxic. The findings suggest that MDMA must be metabolized into these catechol compounds for cardiotoxicity to occur in isolated heart cells.
Chemical Research in Toxicology
May 1, 1992
L.y. Lin, Yoshito Kumagai, Arthur K. Cho
67 citations
Rat brain microsomes convert MDA and MDMA into dihydroxyamphetamine (DHA) and dihydroxymethamphetamine (DHMA), respectively. This demethylenation requires NADPH and is strongly inhibited by carbon monoxide/oxygen, indicating involvement of cytochrome P450. The process is inhibited by desipramine, imipramine, and methimazole but not by SKF-525A or alpha-naphthoflavone. Biphasic Lineweaver-Burk plots suggest multiple isozymes may be involved, and no significant stereoselectivity is observed. Catechol formation is 2.6 times greater in phosphate buffer than HEPES buffer, but this difference disappears with desferal and hydroxyl radical scavengers. Sensitivity to catalase and stimulation by ferric ion and EDTA indicate both a cytochrome P450-mediated component and a chemical component involving hydroxyl radicals.
Chemical Research in Toxicology
January 1, 1996
R. Timothy Miller, Serrine S. Lau, Terrence J. Monks
63 citations
The metabolite 5-(glutathion-S-yl)-alpha-methyldopamine, formed from the oxidation of alpha-methyldopamine in the presence of glutathione, reproduces several acute behavioral and neurochemical effects of the serotonergic neurotoxicants MDA and MDMA in rats. Intracerebroventricular injection of this conjugate caused hyperactivity, aggression, forepaw treading, and Straub tail—behaviors typical of serotonin release. It also produced short-term changes in dopaminergic, serotonergic, and noradrenergic systems, including increased dopamine synthesis and acute serotonin turnover, as well as depletion of brain norepinephrine similar to MDA's pressor effect. However, a single injection did not cause long-term serotonergic toxicity, suggesting that while acute dopamine turnover may be necessary for such toxicity, it is not sufficient on its own.
Chemical Research in Toxicology
May 31, 2001
Fengju Bai, Douglas C. Jones, Serrine S. Lau et al.
56 citations
Reactive metabolites, particularly 5-(glutathion-S-yl)-alpha-methyldopamine (5-GSyl-alpha-MeDA), contribute to the serotonergic neurotoxicity caused by the drugs MDA and MDMA (ecstasy). Inhibiting the enzyme gamma-glutamyl transpeptidase (gamma-GT) at the blood-brain barrier with acivicin increased the brain uptake of these thioether metabolites and worsened the depletion of serotonin and its metabolite 5-HIAA in brain regions rich in serotonin nerve terminals. Acivicin pretreatment also increased glial fibrillary acidic protein (GFAP) expression in the striatum when combined with MDA, indicating enhanced neurotoxicity. The findings suggest that thioether metabolites formed from MDA and MDMA are key contributors to the serotonergic damage seen after peripheral drug administration.
Chemical Research in Toxicology
May 22, 2009
Markus R. Meyer, Hans H. Maurer
39 citations
The designer drugs MDMA, MDEA, and MBDB are chiral compounds whose metabolism is enantioselective, favoring the S-enantiomer. This study investigated whether the elimination of their catecholamine metabolites via O-methylation by catechol-O-methyltransferase (COMT) is also enantioselective. Using human liver cytosol and microsomes, the S-enantiomers of all three catecholamines were preferentially O-methylated by both soluble and membrane-bound COMT. The membrane-bound COMT had 10-fold higher affinity for substrates, while the soluble form had 10-fold higher turnover rate. All tested catechols uncompetitively inhibited dopamine methylation. Enantioselective elimination may contribute to different pharmacokinetic properties of the enantiomers.