Journal
BIOCHEMICAL PHARMACOLOGY
Volume 59, Issue 12, Pages 1563-1571Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0006-2952(00)00284-7
Keywords
CYP2D6; cytochrome P450; designer drugs; ecstasy; MDE; MDMA
Categories
Ask authors/readers for more resources
The human cytochrome P450 (CYP) isozymes catalyzing the oxidative metabolism of the widely abused amphetamine derivatives MDMA (N-methyl-3,4-mechylenedioxyamphetamine, Ecstasy), MDE (Nethyl-3,4-methylenedioxyampheramine, Eve), and MDA (3,4-mechylenedioxyamphetamine) 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. (C) 2000 Elsevier Science Inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available