Identification of the human cytochromes P450 involved in the oxidative metabolism of "Ecstasy"-related designer drugs.
K Kreth, K Kovar, M Schwab, U M Zanger
Biochemical Pharmacology June 15, 2000 DOI: 10.1016/s0006-2952(00)00284-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory in vitro study Peer reviewed |
|---|---|
| Population | Human liver microsomes, including samples from a CYP2D6 extensive metabolizer and a poor metabolizer, plus a panel of 12 human livers and recombinant P450 enzymes |
| Topics | MDMA |
| Key points | CYP2D6 is the sole high-affinity enzyme demethylenating MDMA, MDE, and MDA, while CYP1A2 is the major low-affinity demethylenase with contributions from CYP2B6 and CYP3A4. N-dealkylation is at least 7-fold slower than demethylenation and is linked mainly to CYP2B6. The authors conclude that other P450 isozymes can contribute to methylenedioxyamphetamine metabolism, which may matter in people lacking functional CYP2D6. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 53
- Human Pharmacology of MDMA Therapeutic Drug Monitoring March 19, 2004
- Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy Journal of Psychopharmacology 2005
- Toxicokinetics of Amphetamines: Metabolism and Toxicokinetic Data of Designer Drugs, Amphetamine, Methamphetamine, and Their N-Alkyl Derivatives Therapeutic Drug Monitoring April 1, 2002
- Chemistry, Pharmacology, Toxicology, and Hepatic Metabolism of Designer Drugs of the Amphetamine (Ecstasy), Piperazine, and Pyrrolidinophenone Types Therapeutic Drug Monitoring March 19, 2004
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
and 48 more in the library
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and 10 more in the library