20521-18-0Relevant articles and documents
Identification of the human cytochromes P450 involved in the oxidative metabolism of 'Ecstasy'-related designer drugs
Kreth, Klaus-Peter,Kovar, Karl-Artur,Schwab, Matthias,Zanger, Ulrich M.
, p. 1563 - 1571 (2000)
The human cytochrome P450 (CYP) isozymes catalyzing the oxidative metabolism of the widely abused amphetamine derivatives MDMA (N-methyl-3,4-methylenedioxyamphetamine, 'Ecstasy'), MDE (N-ethyl-3,4-methylenedioxyamphetamine, 'Eve'), and MDA (3,4-methylenedioxyamphetamine) were identified. Using a simplified non-extractive reversed-phase HPLC assay with fluorescence detection, biphasic Michaelis-Menten kinetics were obtained for formation of all three dihydroxyamphetamines in liver microsomes from a CYP2D6 extensive metabolizer subject. In contrast, no low K(m) component was detectable in microsomes from a poor metabolizer subject. Additional specific probes for CYP2D6 further confirmed this isozyme as the exclusive low K(m) component for demethylenation. P450-selective inhibitors applied to CYP2D6-inhibited microsomes and activity measurements in a series of recombinant P450s suggested CYP1A2 as the major high K(m) component with contributions by CYP2B6 and CYP3A4. Moreover, the relative CYP1A2 content of a panel of 12 human livers was weakly but significantly correlated to the high K(m) demethylenase activity (Spearman rank correlation coefficient [r(s)] = 0.58; P 0.05). Microsomal maximal velocities for N-dealkylation were at least 7-fold lower than for demethylenation and were characterized by apparently monophasic kinetics. The most important isozyme for this reaction appeared to be CYP2B6, the microsomal content of which was found to be strongly correlated to N-deethylation of MDE (r(s) = 0.90; P 0.001). We conclude that, in addition to CP2D6 as the sole high-affinity demethylenase, several other P450 isozymes have the capacity to contribute to microsomal oxidative metabolism of methylenedioxyamphetamines. This may be of particular importance in individuals genetically lacking functional CYP2D6. Copyright (C) 2000 Elsevier Science Inc.
Metabolic regio- and stereoselectivity of cytochrome P450 2D6 towards 3,4-methylenedioxy-N-alkylamphetamines: In silico predictions and experimental validation
Keizers, Peter H. J.,De Graaf, Chris,De Kanter, Frans J. J.,Oostenbrink, Chris,Feenstra, K. Anton,Commandeur, Jan N. M.,Vermeulen, Nico P. E.
, p. 6117 - 6127 (2007/10/03)
A series of 3,4-methylenedioxy-N-alkylamphetamines (MDAAs) were automatically docked and subjected to molecular dynamics (MD) simulations in a cytochrome P450 2D6 (CYP2D6) protein model. The predicted substrate binding orientations, sites of oxidation, and relative reactivities were compared to the experimental data of wild-type and Phe120Ala mutant CYP2D6. Automated docking results were not sufficient to accurately rationalize experimental binding orientations of 3,4-methylenedioxy-N-methylamphetamine (MDMA) in the two enzymes as measured with spin lattice relaxation NMR. Nevertheless, the docking results could be used as starting structures for MD simulations. Predicted binding orientations of MDMA and sites of oxidation of the MDAAs derived from MD simulations matched well with the experimental data. It appeared the experimental results were best described in MD simulations considering the nitrogen atoms of the MDAAs in neutral form. Differences in regioselectivity and stereoselectivity in the oxidative metabolism of the MDAAs by the Phe120Ala mutant CYP2D6 were correctly predicted, and the effects of the Phe120Ala mutation could be rationalized as well.
