PMID- 21402137
OWN - NLM
STAT- MEDLINE
DCOM- 20110617
LR  - 20181211
IS  - 1879-3169 (Electronic)
IS  - 0378-4274 (Linking)
VI  - 203
IP  - 1
DP  - 2011 May 30
TI  - 3,4-methylenedioxymethamphetamine (MDMA) interacts with therapeutic drugs on 
      CYP3A by inhibition of pregnane X receptor (PXR) activation and catalytic enzyme 
      inhibition.
PG  - 82-91
LID - 10.1016/j.toxlet.2011.03.007 [doi]
AB  - Metabolism of MDMA (3,4-methylenedioxymethamphetamine, Ecstasy) by the major 
      hepatic drug-metabolizing enzyme cytochrome P450 3A (CYP3A), plays an important 
      role in MDMA-induced liver toxicity. In the present study, we investigated 
      interactions between MDMA and several therapeutic and recreational drugs on CYP3A 
      and its regulator pregnane X receptor (PXR), using a human PXR-mediated 
      CYP3A4-reporter gene assay, rat primary hepatocytes and microsomes. MDMA 
      significantly inhibited hPXR-mediated CYP3A4-reporter gene expression induced by 
      the human PXR activator rifampicin (IC(5)(0) 1.26 +/- 0.36 mM) or the therapeutic drugs 
      paroxetine, fluoxetine, clozapine, diazepam and risperidone. All these drugs 
      concentration-dependently inhibited CYP3A activity in rat liver microsomes, but 
      in combination with MDMA this inhibition became more efficient for clozapine and 
      risperidone. In rat primary hepatocytes that were pretreated with or without the 
      rodent PXR activator pregnenolone 16alpha-carbonitrile (PCN), MDMA inhibited 
      CYP3A catalytic activity with IC(5)(0) values of 0.06 +/- 0.12 and 0.09 +/- 0.13 mM MDMA, 
      respectively. This decrease appeared to be due to decreased activation of PXR and 
      subsequent decreased CYP3A gene expression, and catalytic inhibition of CYP3A 
      activity. These data suggest that in situations of repeated MDMA use in 
      combination with other (therapeutic) drugs, adverse drug-drug interactions 
      through interactions with PXR and/or CYP3A cannot be excluded.
CI  - Copyright (c) 2011 Elsevier Ireland Ltd. All rights reserved.
FAU - Antolino-Lobo, Irene
AU  - Antolino-Lobo I
AD  - Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands. 
      i.antolinolobo@uu.nl
FAU - Meulenbelt, Jan
AU  - Meulenbelt J
FAU - Nijmeijer, Sandra M
AU  - Nijmeijer SM
FAU - Maas-Bakker, Roel F
AU  - Maas-Bakker RF
FAU - Meijerman, Irma
AU  - Meijerman I
FAU - van den Berg, Martin
AU  - van den Berg M
FAU - van Duursen, Majorie B M
AU  - van Duursen MB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110322
PL  - Netherlands
TA  - Toxicol Lett
JT  - Toxicology letters
JID - 7709027
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hallucinogens)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (Receptors, Steroid)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.14.1 (Cyp3a2 protein, rat)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Cytochrome P-450 CYP3A/genetics/metabolism
MH  - *Cytochrome P-450 CYP3A Inhibitors
MH  - *Cytochrome P-450 Enzyme Inhibitors
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Enzyme Inhibitors/*pharmacology
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Hallucinogens/*pharmacology
MH  - Hepatocytes/*drug effects/enzymology
MH  - Humans
MH  - Male
MH  - Microsomes, Liver/drug effects/enzymology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology
MH  - Pregnane X Receptor
MH  - RNA Interference
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Steroid/*antagonists & inhibitors/genetics/metabolism
MH  - Transfection
EDAT- 2011/03/16 06:00
MHDA- 2011/06/18 06:00
CRDT- 2011/03/16 06:00
PHST- 2011/01/21 00:00 [received]
PHST- 2011/03/03 00:00 [revised]
PHST- 2011/03/04 00:00 [accepted]
PHST- 2011/03/16 06:00 [entrez]
PHST- 2011/03/16 06:00 [pubmed]
PHST- 2011/06/18 06:00 [medline]
AID - S0378-4274(11)00106-8 [pii]
AID - 10.1016/j.toxlet.2011.03.007 [doi]
PST - ppublish
SO  - Toxicol Lett. 2011 May 30;203(1):82-91. doi: 10.1016/j.toxlet.2011.03.007. Epub 
      2011 Mar 22.