Catechol-O-methyltransferase and 3,4-(±)-methylenedioxymethamphetamine toxicity

Joseph M. Herndon, Aram B. Cholanians, Lucina E. Lizarraga, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

3 Citations (Scopus)

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, Nmethyl- 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.

Original languageEnglish (US)
Article numberkfu035
Pages (from-to)162-173
Number of pages12
JournalToxicological Sciences
Volume139
Issue number1
DOIs
StatePublished - 2014

Fingerprint

N-Methyl-3,4-methylenedioxyamphetamine
Catechol O-Methyltransferase
Toxicity
Metabolites
Deoxyepinephrine
Catechols
Serotonin
3,4-Methylenedioxyamphetamine
Methylation
Poisons
Genetic Models
Enzymes
Body Temperature
Metabolism
Cytochrome P-450 Enzyme System
Glutathione
Rats
Dopamine
Genes

Keywords

  • 3,4-(±)-methylenedioxymethamphetamine
  • Catechol-O-methyltransferase
  • Hyperthermia

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

Catechol-O-methyltransferase and 3,4-(±)-methylenedioxymethamphetamine toxicity. / Herndon, Joseph M.; Cholanians, Aram B.; Lizarraga, Lucina E.; Lau, Serrine; Monks, Terrence.

In: Toxicological Sciences, Vol. 139, No. 1, kfu035, 2014, p. 162-173.

Research output: Contribution to journalArticle

Herndon, Joseph M. ; Cholanians, Aram B. ; Lizarraga, Lucina E. ; Lau, Serrine ; Monks, Terrence. / Catechol-O-methyltransferase and 3,4-(±)-methylenedioxymethamphetamine toxicity. In: Toxicological Sciences. 2014 ; Vol. 139, No. 1. pp. 162-173.
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