The demethylenation of methylenedioxymethamphetamine (“ecstasy”) by debrisoquine hydroxylase (CYP2D6)

• Published in: Biochemical pharmacology Vol. 47; no. 7; pp. 1151 - 1156
• Main Authors: Tucker, G.T., Lennard, M.S., Ellis, S.W., Woods, H.F., Cho, A.K., Lin, L.Y., Hiratsuka, A., Schmitz, D.A., Chu, T.Y.Y.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 29.03.1994; Elsevier Science
• Subjects: 3,4-Methylenedioxyamphetamine - analogs & derivatives; 3,4-Methylenedioxyamphetamine - metabolism; Biological and medical sciences; brain P450; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; debrisoquine; Deoxyepinephrine - analogs & derivatives; Deoxyepinephrine - analysis; Drug addictions; ecstasy, methylenedioxymethamphetamine; extensive metabolizer; Humans; Kinetics; Male; Medical sciences; Microsomes, Liver - enzymology; Middle Aged; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; N-Methyl-3,4-methylenedioxyamphetamine; NADP - metabolism; neurotoxicity; poor metabolizer; Saccharomyces cerevisiae - enzymology; Toxicology; Transfection; poor metabolizer; neurotoxicity; CYP2D6; DHMA; EM; ecstasy, methylenedioxymethamphetamine; MDA; brain P450; PM; debrisoquine; extensive metabolizer; MDMA; Human; Sensitivity resistance; Enzyme; Isozyme; Cytochrome P450; Toxicogenetics; Metabolism toxicity relation; Drug of abuse; Metabolism; In vitro; Polymorphism
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/0006-2952(94)90386-7

The metabolism of methylenedioxymethamphetamine (MDMA, “ecstasy”) was examined in a microsomal preparation of the yeast Saccharomyces cerevisiae expressing human debrisoquine hydroxylase, CYP2D6. Only one product, dihydroxymethylamphetamine (DHMA), was detected in the incubation mixture, and this product accounted for all of the substrate consumption at low concentration (10μM). Mean ± SD values of apparent K m ( μM) and V max (nmol/min per nmol P450) for the demethylenation of (+) and (−)-MDMA at low concentrations (1–1000 μM) were 1.72, 0.12 and 6.45, 0.10 and 2.90, 0.10 and 7.61, 0.06, respectively. At high concentrations (> 1000 μM) substrate inhibition was noted, with K i values of 14.2 and 28.2 mM, respectively, for the (+) and (−) enantiomers. Incubation of MDMA isomers with human liver microsomes indicated that their demethylenation is deficient in the poor metabolizer phenotype. Thus, MDMA is converted to the catecholamine DHMA by CYP2D6, and this may give rise to genetically-determined differences in toxicity.