Kinetic mechanism of time-dependent inhibition of CYP2D6 by 3,4-methylenedioxymethamphetamine (MDMA): Functional heterogeneity of the enzyme and the reversibility of its inactivation.
John T Rodgers, Nadezhda Y Davydova, Erickson M Paragas, Jeffrey P Jones, Dmitri R Davydov
Biochemical Pharmacology October 2018 DOI: 10.1016/j.bcp.2018.08.010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro mechanistic enzyme kinetics study Peer reviewed |
|---|---|
| Population | Human CYP2D6 expressed in proteoliposomes and insect-cell microsomes (Supersomes) |
| Interventions | 3 4-methylenedioxymethamphetamine (MDMA) |
| Topics | MDMA |
| Keywords | 3,4-methylenedioxymethamphetamine Cytochrome p450 2d6 Mechanism-based inhibition Methylenedioxyphenyl compounds Time-dependent inhibition |
| Key points | The authors report that MDMA forms a ferrous carbene-derived metabolic inhibitory complex with CYP2D6 relatively slowly and reversibly, without accumulation of a ferric carbene intermediate as seen with CYP3A4 and podophyllotoxin. Only about 50% of spectrally detectable CYP2D6 formed the complex, which the authors interpret as functional heterogeneity of the enzyme population and suggest that MDMA-dependent time-dependent inhibition of CYP2D6 may be overestimated in potency and physiological relevance. |
Abstract
We investigate the mechanism of time-dependent inhibition (TDI) of human cytochrome P450 2D6 (CYP2D6) by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), one of the most widespread recreational drugs of abuse. In an effort to unravel the kinetic mechanism of the formation of metabolic inhibitory complex (MIC) of CYP2D6 with MDMA-derived carbene we carried out a series of spectrophotometric studies paralleled with registration of the kinetics of time-dependent inhibition (TDI) in CYP2D6-incorporated proteoliposomes. The high amplitude of spectral signal in this system allowed us to characterize the spectral properties of the formed MIC in details and obtain an accurate spectral signature of MIC formation. This information was then used in the studies with CYP2D6-containing microsomes of insect cells (CYP2D6 Supersomes™). Our results demonstrate that in both systems the formation of the ferrous carbene-derived MIC is relatively slow, reversible and is not associated with the accumulation of the ferric carbene intermediate, as takes place in the case of CYP3A4 and podophylotoxin. Furthermore, the limited amplitude of MIC formation suggests that only a fraction (∼50%) of spectrally detectable CYP2D6 in both proteoliposomes and Supersomes participates in the formation of MIC and is therefore involved in the MDMA metabolism. This observation reveals yet another example of a cytochrome P450 that exhibits persistent functional heterogeneity of its population in microsomal membranes. Our study provides a solid methodological background for further mechanistic studies of MIC formation in human liver microsomes and demonstrates that the potency and physiological relevance of MDMA-dependent TDI of CYP2D6 may be overestimated.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 4
- Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database Frontiers in Psychiatry January 24, 2022
- Concomitant medications associated with ischemic, hypertensive, and arrhythmic events in MDMA users in FDA adverse event reporting system Frontiers in Psychiatry May 18, 2023
- Hepatic injury and hepatic failure adverse events in 3,4-methylenedioxymethamphetamine users reported to the FDA Adverse Event Reporting System. Frontiers in Psychiatry 2024
- Cross-species metabolic characterization of eutylone and mechanism-based inhibition of CYP2D6 and CYP2B6 with drug interaction implications. Scientific Reports April 16, 2026
Cites 4
- Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA Journal of Psychopharmacology May 20, 2006
- The Consequences of 3,4-Methylenedioxymethamphetamine Induced CYP2D6 Inhibition in Humans Journal of Clinical Psychopharmacology September 12, 2008
- Mechanisms underlying the hepatotoxic effects of ecstasy. Current Pharmaceutical Biotechnology August 1, 2010
- Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics. Psychopharmacology May 2004