PMID- 24177245
OWN - NLM
STAT- MEDLINE
DCOM- 20140930
LR  - 20140130
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 88
IP  - 2
DP  - 2014 Feb
TI  - "Ecstasy"-induced toxicity in SH-SY5Y differentiated cells: role of hyperthermia 
      and metabolites.
PG  - 515-31
LID - 10.1007/s00204-013-1147-9 [doi]
AB  - 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a recreational 
      hallucinogenic drug of abuse known to elicit neurotoxic properties. Hepatic 
      formation of neurotoxic metabolites is thought to play a major role in 
      MDMA-related neurotoxicity, though the mechanisms involved are still unclear. 
      Here, we studied the neurotoxicity mechanisms and stability of MDMA and 6 of its 
      major human metabolites, namely alpha-methyldopamine (alpha-MeDA) and 
      N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and their correspondent glutathione (GSH) 
      and N-acetyl-cysteine (NAC) conjugates, under normothermic (37  degrees C) or 
      hyperthermic conditions (40  degrees C), using cultured SH-SY5Y differentiated cells. We 
      showed that MDMA metabolites exhibited toxicity to SH-SY5Y differentiated cells, 
      being the GSH and NAC conjugates more toxic than their catecholic precursors and 
      MDMA. Furthermore, whereas the toxicity of the catechol metabolites was 
      potentiated by hyperthermia, NAC-conjugated metabolites revealed higher toxicity 
      under normothermia and GSH-conjugated metabolites-induced toxicity was 
      temperature-independent. Moreover, a time-dependent decrease in extracellular 
      concentration of MDMA metabolites was observed, which was potentiated by 
      hyperthermia. The antioxidant NAC significantly protected against the neurotoxic 
      effects of MDMA metabolites. MDMA metabolites increased intracellular glutathione 
      levels, though depletion in thiol content was observed in MDMA-exposed cells. 
      Finally, the neurotoxic effects induced by the MDMA metabolite N-Me-alpha-MeDA 
      involved caspase 3 activation. In conclusion, this study evaluated the stability 
      of MDMA metabolites in vitro, and demonstrated that the catechol MDMA metabolites 
      and their GSH and NAC conjugates, rather than MDMA itself, exhibited neurotoxic 
      actions in SH-SY5Y differentiated cells, which were differently affected by 
      hyperthermia, thus highlighting a major role for reactive metabolites and 
      hyperthermia in MDMA's neurotoxicity.
FAU - Barbosa, Daniel Jose
AU  - Barbosa DJ
AD  - REQUIMTE (Rede de Quimica e Tecnologia), Toxicology Laboratory, Department of 
      Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo 
      Ferreira 228, 4050-313, Porto, Portugal, daniel.barbosa@ff.up.pt.
FAU - Capela, Joao Paulo
AU  - Capela JP
FAU - Silva, Renata
AU  - Silva R
FAU - Ferreira, Luisa Maria
AU  - Ferreira LM
FAU - Branco, Paula Serio
AU  - Branco PS
FAU - Fernandes, Eduarda
AU  - Fernandes E
FAU - Bastos, Maria Lourdes
AU  - Bastos ML
FAU - Carvalho, Felix
AU  - Carvalho F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131101
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - 555-64-6 (alpha-methyldopamine)
RN  - EC 3.4.22.- (Caspase 3)
RN  - GAN16C9B8O (Glutathione)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - R7339QLN1C (Deoxyepinephrine)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/metabolism/toxicity
MH  - Acetylcysteine/metabolism/pharmacology
MH  - Caspase 3/metabolism
MH  - Cell Death/drug effects
MH  - Cell Differentiation/*drug effects
MH  - Cell Line/drug effects
MH  - Deoxyepinephrine/analogs & derivatives/metabolism/toxicity
MH  - Fever/*chemically induced/metabolism
MH  - Glutathione/metabolism
MH  - Humans
MH  - Mitochondria/drug effects/metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*metabolism/pharmacokinetics/*toxicity
MH  - Neurons/*drug effects/metabolism
MH  - Neurotoxicity Syndromes/metabolism/pathology
MH  - Temperature
EDAT- 2013/11/02 06:00
MHDA- 2014/10/01 06:00
CRDT- 2013/11/02 06:00
PHST- 2013/08/13 00:00 [received]
PHST- 2013/10/07 00:00 [accepted]
PHST- 2013/11/02 06:00 [entrez]
PHST- 2013/11/02 06:00 [pubmed]
PHST- 2014/10/01 06:00 [medline]
AID - 10.1007/s00204-013-1147-9 [doi]
PST - ppublish
SO  - Arch Toxicol. 2014 Feb;88(2):515-31. doi: 10.1007/s00204-013-1147-9. Epub 2013 
      Nov 1.