PMID- 21871945
OWN - NLM
STAT- MEDLINE
DCOM- 20111102
LR  - 20131121
IS  - 1879-3185 (Electronic)
IS  - 0300-483X (Linking)
VI  - 289
IP  - 2-3
DP  - 2011 Nov 18
TI  - Induction of glutathione synthesis and conjugation by 
      3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dihydroxymethamphetamine (HHMA) 
      in human and rat liver cells, including the protective role of some antioxidants.
PG  - 175-84
LID - 10.1016/j.tox.2011.08.012 [doi]
AB  - MDMA (3,4-methylenedioxymethamphetamine) metabolism is a major cause of 
      MDMA-mediated hepatotoxicity. In this study the effects of MDMA and its 
      metabolites on the glutathione system were evaluated. Glutathione (GSH/GSSG) 
      levels and gene expression of glutamate cysteine ligase catalytic subunit (GCLC), 
      glutathione-S-transferase (GST) and pregnane X receptor (PXR) were compared in 
      the immortalized human liver epithelial cell line THLE-Neo lacking phase I 
      metabolism and primary rat hepatocytes expressing both phase I and II metabolism. 
      Furthermore, we evaluated the potential protective effects of two antioxidants, 
      N-acetyl-cysteine (NAC) and sulforaphane (SFN) in these cell systems. In THLE-Neo 
      cells, the MDMA metabolite 3,4-dihydroxymetamphetamine (HHMA) significantly 
      decreased cell viability and depleted GSH levels, resulting in an increased 
      expression of GCLC and GST up to 3.4- and 2.2-fold, respectively. In primary rat 
      hepatocytes, cell viability or GSH levels were not significantly affected upon 
      MDMA exposure. GCLC expression levels where not significantly altered either, 
      although GST expression was increased 2.3-fold. NAC counteracted MDMA-induced 
      cytotoxicity and restored GSH levels. Phase II enzyme expression was also 
      reverted. Conversely, SFN increased MDMA-induced cytotoxicity and GSH depletion, 
      while GCLC and GST expression were significantly induced. In addition, PXR 
      expression decreased after HHMA and MDMA exposure, while co-exposure to SFN 
      induced it up to 3.6- and 3.9-fold compared to vehicle-control in the THLE-Neo 
      cells and rat hepatocytes, respectively. Taken together, these data indicate that 
      HHMA is a major factor in the MDMA-mediated hepatotoxicity through interaction 
      with the glutathione system. The results of our study show that for MDMA 
      intoxication the treatment with an antioxidant such as NAC may counteract the 
      potentially hepatotoxicity. However, SFN supplementation should be considered 
      with care because of the indications of possible drug-drug interactions.
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 - Molendijk, Jeffrey
AU  - Molendijk 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  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110817
PL  - Ireland
TA  - Toxicology
JT  - Toxicology
JID - 0361055
RN  - 0 (Antioxidants)
RN  - 0 (Protective Agents)
RN  - 15398-87-5 (alpha-methylepinine)
RN  - GAN16C9B8O (Glutathione)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - R7339QLN1C (Deoxyepinephrine)
SB  - IM
MH  - Animals
MH  - Antioxidants/metabolism/*pharmacology
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Deoxyepinephrine/*analogs & derivatives/metabolism/toxicity
MH  - Drug Interactions/physiology
MH  - Glutathione/*biosynthesis/metabolism
MH  - Hepatocytes/*drug effects/metabolism
MH  - Humans
MH  - Male
MH  - N-Methyl-3,4-methylenedioxyamphetamine/metabolism/*toxicity
MH  - Protective Agents/metabolism/*pharmacology
MH  - Rats
MH  - Rats, Wistar
EDAT- 2011/08/30 06:00
MHDA- 2011/11/04 06:00
CRDT- 2011/08/30 06:00
PHST- 2011/07/09 00:00 [received]
PHST- 2011/08/09 00:00 [revised]
PHST- 2011/08/10 00:00 [accepted]
PHST- 2011/08/30 06:00 [entrez]
PHST- 2011/08/30 06:00 [pubmed]
PHST- 2011/11/04 06:00 [medline]
AID - S0300-483X(11)00303-9 [pii]
AID - 10.1016/j.tox.2011.08.012 [doi]
PST - ppublish
SO  - Toxicology. 2011 Nov 18;289(2-3):175-84. doi: 10.1016/j.tox.2011.08.012. Epub 
      2011 Aug 17.