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The demethylenation of methylenedioxymethamphetamine ("ecstasy") by debrisoquine hydroxylase (CYP2D6)

G T Tucker1, M S Lennard, S W Ellis

  • 1Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital, U.K.

Biochemical Pharmacology
|March 29, 1994
PubMed

Insights

Methylenedioxymethamphetamine (MDMA) is metabolized to dihydroxymethylamphetamine (DHMA) by the enzyme CYP2D6. Genetic variations in CYP2D6 can affect MDMA metabolism and potentially influence its toxicity.

Area of Science:

  • Pharmacology
  • Enzymology
  • Toxicology

Background:

  • Methylenedioxymethamphetamine (MDMA) is a psychoactive drug with complex metabolism.
  • Cytochrome P450 2D6 (CYP2D6) is a key enzyme involved in drug metabolism.
  • Genetic polymorphisms in CYP2D6 can lead to significant inter-individual variability in drug response and toxicity.

Purpose of the Study:

  • To investigate the metabolic pathway of MDMA using a yeast expression system.
  • To characterize the kinetic parameters of MDMA demethylenation by CYP2D6.
  • To explore the implications of CYP2D6-mediated MDMA metabolism on potential toxicity.

Main Methods:

  • Utilized Saccharomyces cerevisiae microsomes engineered to express human CYP2D6.
  • Incubated MDMA enantiomers with the microsomes and analyzed metabolic products using chromatography.
  • Determined kinetic parameters (Km, Vmax, Ki) for MDMA demethylenation.
  • Compared MDMA metabolism in human liver microsomes from individuals with different CYP2D6 metabolizer phenotypes.

Main Results:

  • CYP2D6 efficiently demethylenated both (+) and (-)-MDMA to form dihydroxymethylamphetamine (DHMA).
  • Apparent Km and Vmax values indicated stereoselective metabolism of MDMA.
  • Substrate inhibition was observed at high MDMA concentrations.
  • MDMA demethylenation was significantly reduced in human liver microsomes from poor metabolizers of CYP2D6.

Conclusions:

  • CYP2D6 is the primary enzyme responsible for the conversion of MDMA to DHMA.
  • The rate of MDMA metabolism by CYP2D6 is enantioselective and subject to substrate inhibition.
  • Deficient CYP2D6 activity in poor metabolizers may alter MDMA's metabolic profile and contribute to genetically determined differences in toxicity.

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