Influence of CYP2D6 polymorphism on 3,4-methylenedioxymethamphetamine ('Ecstasy') cytotoxicity
by
Carmo H, Brulport M, Hermes M, Oesch F, Silva R, Ferreira LM, Branco PS, Boer DD, Remiao F, Carvalho F, Schon MR, Krebsfaenger N, Doehmer J, Bastos MD, Hengstler JG.
aREQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Porto bREQUIMTE/CQFB, Chemistry Department, Faculty of Science and Technology, University Nova of Lisboa, Monte de Caparica, Portugal cCentre for Toxicology dDepartment of Surgery, University of Leipzig, Leipzig eSchwarz Biosciences GmbH, Department of Pharmacology and Toxicology, Monheim fGenPharmTox BioTech AG, D-Planegg/Martinsried gInstitute of Toxicology, University of Mainz, Mainz, Germany hDepartment of Clinical Chemistry, University Hospital Maastricht, Maastricht, The Netherlands.
Pharmacogenet Genomics. 2006 Nov;16(11):789-799.


ABSTRACT

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.

P450 (CYP) 2D6
Protect and survive
MDMA and immunity
Ecstasy and serotonin synthesis
N-hydroxylated metabolites of MDMA (Ecstasy)
Role of Cytochrome P450 (CYP) 2D6 in MDMA metabolism


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