PMID- 23670916
OWN - NLM
STAT- MEDLINE
DCOM- 20141208
LR  - 20161125
IS  - 1099-1263 (Electronic)
IS  - 0260-437X (Linking)
VI  - 34
IP  - 6
DP  - 2014 Jun
TI  - Mixtures of 3,4-methylenedioxymethamphetamine (ecstasy) and its major human 
      metabolites act additively to induce significant toxicity to liver cells when 
      combined at low, non-cytotoxic concentrations.
PG  - 618-27
LID - 10.1002/jat.2885 [doi]
AB  - Hepatic injury after 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) 
      intoxications is highly unpredictable and does not seem to correlate with either 
      dosage or frequency of use. The mechanisms involved include the drug metabolic 
      bioactivation and the hyperthermic state of the liver triggered by its 
      thermogenic action and exacerbated by the environmental circumstances of abuse at 
      hot and crowded venues. We became interested in understanding the interaction 
      between ecstasy and its metabolites generated in vivo as users are always exposed 
      to mixtures of parent drug and metabolites. With this purpose, Hep G2 cells were 
      incubated with MDMA and its main human metabolites methylenedioxyamphetamine 
      (MDA), alpha-methyldopamine (alpha-MeDA) and N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA), 
      individually and in mixture (drugs combined in proportion to their individual 
      EC01 ), at normal (37  degrees C) and hyperthermic (40.5  degrees C) conditions. After 48 h, 
      viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl 
      tetrazolium bromide (MTT) assay. Extensive concentration-response analysis was 
      performed with single drugs and the parameters of the individual non-linear logit 
      fits were used to predict joint effects using the well-founded models of 
      concentration addition (CA) and independent action (IA). Experimental testing 
      revealed that mixture effects on cell viability conformed to CA, for both 
      temperature settings. Additionally, substantial combination effects were attained 
      even when each substance was present at concentrations that individually produced 
      unnoticeable effects. Hyperthermic incubations dramatically increased the 
      toxicity of the tested drug and metabolites, both individually and combined. 
      These outcomes suggest that MDMA metabolism has hazard implications to liver 
      cells even when metabolites are found in low concentrations, as they contribute 
      additively to the overall toxic effect of MDMA.
CI  - Copyright (c) 2013 John Wiley & Sons, Ltd.
FAU - da Silva, Diana Dias
AU  - da Silva DD
AD  - Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal; Institute 
      for the Environment, Brunel University, Uxbridge, Middlesex UB8 3PH, United 
      Kingdom; REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, 
      Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
FAU - Silva, Elisabete
AU  - Silva E
FAU - Carvalho, Felix
AU  - Carvalho F
FAU - Carmo, Helena
AU  - Carmo H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130514
PL  - England
TA  - J Appl Toxicol
JT  - Journal of applied toxicology : JAT
JID - 8109495
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - 555-64-6 (alpha-methyldopamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - R7339QLN1C (Deoxyepinephrine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/metabolism/toxicity
MH  - Biotransformation
MH  - Cell Survival/drug effects
MH  - Chemical and Drug Induced Liver Injury/*etiology/metabolism/pathology
MH  - Deoxyepinephrine/analogs & derivatives/metabolism/toxicity
MH  - Dose-Response Relationship, Drug
MH  - Hep G2 Cells
MH  - Hepatocytes/*drug effects/metabolism/pathology
MH  - Humans
MH  - N-Methyl-3,4-methylenedioxyamphetamine/metabolism/*toxicity
MH  - Nonlinear Dynamics
MH  - Risk Assessment
MH  - Temperature
MH  - Time Factors
OTO - NOTNLM
OT  - 3,4-methylenedioxymethamphetamine (MDMA
OT  - concentration addition (CA)
OT  - ecstasy)
OT  - hyperthermia
OT  - independent action (IA)
OT  - metabolites
OT  - mixture effects
EDAT- 2013/05/15 06:00
MHDA- 2014/12/15 06:00
CRDT- 2013/05/15 06:00
PHST- 2013/02/19 00:00 [received]
PHST- 2013/03/08 00:00 [revised]
PHST- 2013/03/18 00:00 [accepted]
PHST- 2013/05/15 06:00 [entrez]
PHST- 2013/05/15 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
AID - 10.1002/jat.2885 [doi]
PST - ppublish
SO  - J Appl Toxicol. 2014 Jun;34(6):618-27. doi: 10.1002/jat.2885. Epub 2013 May 14.