Influence of CYP2D6 polymorphism on 3,4-methylenedioxymethamphetamine ('Ecstasy') cytotoxicity

Pharmacogenet Genomics. 2006 Nov;16(11):789-99. doi: 10.1097/01.fpc.0000230419.05221.fc.


Objectives: Remarkable interindividual differences in 3,4-methylenedioxymethamphetamine ('Ecstasy')-mediated toxicity have been reported in humans. Therefore, we tested whether CYP2D6 or its variant alleles as well as CYP3A4 influence the susceptibility to 3,4-methylenedioxymethamphetamine.

Methods: 3,4-Methylenedioxymethamphetamine cytotoxicity was determined in V79 cells expressing human wild-type CYP2D6 (CYP2D6*1), the low-activity alleles CYP2D6*2, *9, *10, and *17, as well as human CYP3A4. Metabolites of 3,4-methylenedioxymethamphetamine formed by the different cell lines were quantified by high-performance liquid chromatography/electrochemical detector.

Results: Toxicity of 3,4-methylenedioxymethamphetamine was clearly increased in cells expressing CYP2D6*1 compared with the parental cells devoid of CYP-dependent enzymatic activity. Toxicity in V79 CYP2D6*1 cells was also higher than in V79 cell lines expressing the low-activity alleles CYP2D6*2, *9, *10, or *17. In contrast to CYP2D6, the CYP3A4 isoenzyme did not enhance 3,4-methylenedioxymethamphetamine toxicity. Formation of the oxidative 3,4-methylenedioxymethamphetamine metabolite N-methyl-alpha-methyldopamine was greatly enhanced in V79 cell line transfected with CYP2D6*1 compared to all other cell lines. The increase in the cytotoxic effects of 3,4-methylenedioxymethamphetamine observed in this cell line was therefore suspected to be a consequence of the production of this metabolite. This was further investigated by testing the cytotoxicity of N-methyl-alpha-methyldopamine to the control cell line. The results confirmed our hypothesis as the metabolite proved to be more than 100-fold more toxic than the parent compound 3,4-methylenedioxymethamphetamine.

Conclusions: CYP2D6*1 mediates 3,4-methylenedioxymethamphetamine toxicity via formation of N-methyl-alpha-methyldopamine. Therefore, it will be important to investigate whether CYP2D6 ultrarapid metabolizers are overrepresented in the cases of 3,4-methylenedioxymethamphetamine intoxications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Catalysis
  • Cell Line
  • Cricetinae
  • Cytochrome P-450 CYP2D6 / genetics*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics
  • Deoxyepinephrine / analogs & derivatives
  • Deoxyepinephrine / pharmacology
  • Dose-Response Relationship, Drug
  • Hallucinogens / pharmacology
  • Hallucinogens / toxicity*
  • Models, Biological
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacokinetics
  • N-Methyl-3,4-methylenedioxyamphetamine / toxicity*
  • Oxidation-Reduction
  • Polymorphism, Genetic*


  • Hallucinogens
  • alpha-methyldopamine
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Deoxyepinephrine