PMID- 30114388
OWN - NLM
STAT- MEDLINE
DCOM- 20190521
LR  - 20200225
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 156
DP  - 2018 Oct
TI  - Kinetic mechanism of time-dependent inhibition of CYP2D6 by 
      3,4-methylenedioxymethamphetamine (MDMA): Functional heterogeneity of the enzyme 
      and the reversibility of its inactivation.
PG  - 86-98
LID - S0006-2952(18)30330-7 [pii]
LID - 10.1016/j.bcp.2018.08.010 [doi]
AB  - 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 ( approximately 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.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Rodgers, John T
AU  - Rodgers JT
AD  - Department of Chemistry, Washington State University, Pullman, WA 99164, USA.
FAU - Davydova, Nadezhda Y
AU  - Davydova NY
AD  - Department of Chemistry, Washington State University, Pullman, WA 99164, USA.
FAU - Paragas, Erickson M
AU  - Paragas EM
AD  - Department of Chemistry, Washington State University, Pullman, WA 99164, USA.
FAU - Jones, Jeffrey P
AU  - Jones JP
AD  - Department of Chemistry, Washington State University, Pullman, WA 99164, USA.
FAU - Davydov, Dmitri R
AU  - Davydov DR
AD  - Department of Chemistry, Washington State University, Pullman, WA 99164, USA; 
      Institute of Biomedical Chemistry, 10 Pogodinskaya Str, Moscow 119121, Russia. 
      Electronic address: d.davydov@wsu.edu.
LA  - eng
GR  - R01 GM104178/GM/NIGMS NIH HHS/United States
GR  - R01 GM114369/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180813
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Cytochrome P-450 CYP2D6 Inhibitors)
RN  - 0 (Serotonin Agents)
RN  - 7355X3ROTS (Dextromethorphan)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Cytochrome P-450 CYP2D6/*metabolism
MH  - Cytochrome P-450 CYP2D6 Inhibitors/*pharmacology
MH  - Dextromethorphan/metabolism/pharmacology
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Humans
MH  - Kinetics
MH  - Molecular Structure
MH  - N-Methyl-3,4-methylenedioxyamphetamine/chemistry/*pharmacology
MH  - Serotonin Agents/*pharmacology
PMC - PMC6512342
MID - NIHMS1503583
OTO - NOTNLM
OT  - 3,4-methylenedioxymethamphetamine
OT  - Cytochrome P450 2D6
OT  - Mechanism-based inhibition
OT  - Methylenedioxyphenyl compounds
OT  - Time-dependent inhibition
COIS- Conflict of interest The authors have no conflict of interest to declare.
EDAT- 2018/08/17 06:00
MHDA- 2019/05/22 06:00
PMCR- 2019/10/01
CRDT- 2018/08/17 06:00
PHST- 2018/06/10 00:00 [received]
PHST- 2018/08/08 00:00 [accepted]
PHST- 2018/08/17 06:00 [pubmed]
PHST- 2019/05/22 06:00 [medline]
PHST- 2018/08/17 06:00 [entrez]
PHST- 2019/10/01 00:00 [pmc-release]
AID - S0006-2952(18)30330-7 [pii]
AID - 10.1016/j.bcp.2018.08.010 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2018 Oct;156:86-98. doi: 10.1016/j.bcp.2018.08.010. Epub 2018 
      Aug 13.