PMID- 20388857
OWN - NLM
STAT- MEDLINE
DCOM- 20101012
LR  - 20131121
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 38
IP  - 7
DP  - 2010 Jul
TI  - Differential roles of phase I and phase II enzymes in 
      3,4-methylendioxymethamphetamine-induced cytotoxicity.
PG  - 1105-12
LID - 10.1124/dmd.110.032359 [doi]
AB  - Metabolism plays an important role in the toxic effects caused by 
      3,4-methylenedioxymethamphetamine (MDMA). Most research has focused on the 
      involvement of CYP2D6 enzyme in MDMA bioactivation, and less is known about the 
      contribution of other cytochrome P450 (P450) and phase II metabolism. In this 
      study, we researched the differential roles of phase I P450 enzymes CYP1A2, 
      CYP3A4, and CYP2D6 and phase II enzymes glutathione S-transferase (GST) and 
      catechol-O-methyltransferase (COMT) on the toxic potential of MDMA. MDMA acts as 
      inhibitor of its own metabolism with a relative potency of inhibition of 
      CYP2D>CYP3A>> CYP1A in rat liver microsomes and in human liver [immortalized 
      human liver epithelial cells (THLE)] cells transfected with individual CYP1A2, 
      CYP3A4, or CYP2D6. Cytotoxicity measurements [by 
      3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] in THLE cells 
      showed that the inhibition of phase I enzymes CYP1A2 by alpha-naphthoflavone and 
      CYP3A4 by troleandomycin does not affect MDMA-induced cytotoxicity. MDMA 
      metabolism by CYP2D6 significantly increased cytotoxicity, which was counteracted 
      by CYP2D6 inhibition by quinidine. Inhibition of COMT by 
      2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone (Ro-41-0960) and GST by buthionine 
      sulfoximine showed that COMT is mainly involved in detoxification of 
      CYP2D6-formed MDMA metabolites, whereas glutathione (GSH) is mainly involved in 
      detoxification of CYP3A4-formed MDMA metabolites. Liquid chromatography/tandem 
      mass spectrometry analyses of MDMA-metabolites in the THLE cell culture media 
      confirmed formation of the specific MDMA metabolites and corroborated the 
      observed cytotoxicity. Our data suggest that CYP2D6 as well as CYP3A4 play an 
      important role in MDMA bioactivation. In addition, further studies are needed to 
      address the differential roles of CYP3A4 and GSH/GST in MDMA bioactivation and 
      detoxification.
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 - Scherpenisse, Peter
AU  - Scherpenisse P
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 - 20100413
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Enzyme Inhibitors)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Cell Line, Transformed
MH  - Cell Survival/*drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - Humans
MH  - Male
MH  - Metabolic Detoxication, Phase I/genetics/*physiology
MH  - Metabolic Detoxication, Phase II/*physiology
MH  - Microsomes, Liver/drug effects/enzymology
MH  - Models, Biological
MH  - N-Methyl-3,4-methylenedioxyamphetamine/adverse effects/*metabolism
MH  - Rats
EDAT- 2010/04/15 06:00
MHDA- 2010/10/13 06:00
CRDT- 2010/04/15 06:00
PHST- 2010/04/15 06:00 [entrez]
PHST- 2010/04/15 06:00 [pubmed]
PHST- 2010/10/13 06:00 [medline]
AID - dmd.110.032359 [pii]
AID - 10.1124/dmd.110.032359 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2010 Jul;38(7):1105-12. doi: 10.1124/dmd.110.032359. Epub 2010 
      Apr 13.