TY - JOUR
T1 - Influence of CYP2D6 polymorphism on 3,4-methylenedioxymethamphetamine ('Ecstasy') cytotoxicity
AU - Carmo, Helena
AU - Brulport, Marc
AU - Hermes, Matthias
AU - Oesch, Franz
AU - Silva, Renata
AU - Ferreira, Luísa M.
AU - Branco, Paula S.
AU - Boer, Douwe De
AU - Remião, Fernando
AU - Carvalho, Félix Dias
AU - Schön, Michael R.
AU - Krebsfaenger, Niels
AU - Doehmer, Johannes
AU - Bastos, Maria De Lourdes
AU - Hengstler, Jan G.
PY - 2006/11
Y1 - 2006/11
N2 - 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-α-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-α- 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-α-methyldopamine. Therefore, it will be important to investigate whether CYP2D6 ultrarapid metabolizers are overrepresented in the cases of 3,4-methylenedioxymethamphetamine intoxications.
AB - 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-α-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-α- 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-α-methyldopamine. Therefore, it will be important to investigate whether CYP2D6 ultrarapid metabolizers are overrepresented in the cases of 3,4-methylenedioxymethamphetamine intoxications.
KW - 3,4- methylenedioxymethamphetamine
KW - CYP2D6
KW - Ecstasy toxicity
KW - Metabolism
KW - Polymorphism
UR - http://www.scopus.com/inward/record.url?scp=33750289167&partnerID=8YFLogxK
U2 - 10.1097/01.fpc.0000230419.05221.fc
DO - 10.1097/01.fpc.0000230419.05221.fc
M3 - Article
C2 - 17047487
SN - 1744-6872
VL - 16
SP - 789
EP - 799
JO - Pharmacogenetics And Genomics
JF - Pharmacogenetics And Genomics
IS - 11
ER -