Catechol-o-methyltransferase and 3,4-({+/-})-methylenedioxymethamphetamine toxicity.
Joseph M Herndon, Aram B Cholanians, Lucina E Lizarraga, Serrine S. Lau, Terrence J. Monks
Toxicological sciences : an official journal of the Society of Toxicology May 2014 DOI: 10.1093/toxsci/kfu035 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Rats and wild-type and COMT-deficient mice |
| Intervention | MDMA |
| Topics | MDMA |
| Keywords | 3,4-±-methylenedioxymethamphetamine Catechol-o-methyltransferase Hyperthermia |
| Key findings | The authors report that COMT activity shapes MDMA toxicity. Pharmacological COMT inhibition in rats worsened MDMA-induced serotonin deficits and acute hyperthermia. COMT-deficient mice showed greater MDMA-induced dopamine reductions than wild-type mice, and were far more susceptible to acute hyperthermia that resulted in death; neither mouse group showed serotonin decreases. |
Abstract
Metabolism of 3,4-(±)-methylenedioxymethamphetamine (MDMA) is necessary to elicit its neurotoxic effects. Perturbations in phase I and phase II hepatic enzymes can alter the neurotoxic profile of systemically administered MDMA. In particular, catechol-O-methyltransferase (COMT) plays a critical role in determining the fraction of MDMA that is converted to potentially neurotoxic metabolites. Thus, cytochrome P450 mediated demethylenation of MDMA, or its N-demethylated metabolite, 3,4-(±)-methylenedioxyamphetamine, give rise to the catechols, N-methyl-α-methyldopamine and α-methyldopamine, respectively. Methylation of these catechols by COMT limits their oxidation and conjugation to glutathione, a process that ultimately gives rise to neurotoxic metabolites. We therefore determined the effects of modulating COMT, a critical enzyme involved in determining the fraction of MDMA that is converted to potentially neurotoxic metabolites, on MDMA-induced toxicity. Pharmacological inhibition of COMT in the rat potentiated MDMA-induced serotonin deficits and exacerbated the acute MDMA-induced hyperthermic response. Using a genetic mouse model of COMT deficiency, in which mice lack a functional COMT gene, such mice displayed greater reductions in dopamine concentrations relative to their wild-type (WT) counterparts. Neither WT nor COMT deficient mice were susceptible to MDMA-induced decreases in serotonin concentrations. Interestingly, mice devoid of COMT were far more susceptible to the acute hyperthermic effects of MDMA, exhibiting greater increases in body temperature that ultimately resulted in death. Our findings support the view that COMT plays a pivotal role in determining the toxic response to MDMA.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 4
- Neurotoxicity of MDMA: Main effects and mechanisms. Experimental Neurology October 1, 2021
- The combined effects of 3,4-methylenedioxymethamphetamine (MDMA) and selected substituted methcathinones on measures of neurotoxicity Neurotoxicology and Teratology February 16, 2017
- Of mice and men on MDMA: a translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy'). Brain Research November 14, 2019
- MDMA-Associated Liver Toxicity: Pathophysiology, Management, and Current State of Knowledge. AACN advanced critical care 2019
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