PMID- 30255327
OWN - NLM
STAT- MEDLINE
DCOM- 20191114
LR  - 20191114
IS  - 1432-0738 (Electronic)
IS  - 0340-5761 (Linking)
VI  - 92
IP  - 11
DP  - 2018 Nov
TI  - GC-MS metabolomics reveals disturbed metabolic pathways in primary mouse 
      hepatocytes exposed to subtoxic levels of 3,4-methylenedioxymethamphetamine 
      (MDMA).
PG  - 3307-3323
LID - 10.1007/s00204-018-2314-9 [doi]
AB  - 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a well-known hepatotoxic 
      drug. Although its toxicity has been thoroughly studied at high concentrations, 
      there is still insufficient knowledge on possible alterations of cell function at 
      subtoxic concentrations, which are in fact more representative concentrations of 
      intoxication scenarios. In this study, a gas chromatography-mass spectrometry 
      (GC-MS) metabolomics approach was used to investigate the metabolic changes in 
      primary mouse hepatocytes (PMH) exposed to two subtoxic concentrations of MDMA 
      (LC(01) and LC(10)) for 24 h. Metabolomic profiling of both intracellular 
      metabolites and volatile metabolites in the extracellular medium of PMH was 
      performed. Multivariate analysis showed that the metabolic pattern of cells 
      exposed to MDMA discriminates from the controls in a concentration-dependent 
      manner. Exposure to LC(10) MDMA induces a significant increase in some 
      intracellular metabolites, including oleic acid and palmitic acid, and a decrease 
      in glutamate, aspartate, 5-oxoproline, fumarate, malate, phosphoric acid, 
      alpha-ketoglutarate and citrate. Extracellular metabolites such as acetophenone, 
      formaldehyde, pivalic acid, glyoxal and 2-butanone were found significantly 
      increased after exposure to MDMA, compared to controls, whereas 4-methylheptane, 
      2,4-dimethyl-1-heptene, nonanal, among others, were found significantly 
      decreased. The panel of discriminatory metabolites is mainly involved in 
      tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamate metabolism, 
      antioxidant defenses and possibly changes in the liver enzyme machinery. Overall, 
      these results highlight the potential of the intra- and extracellular metabolome 
      to study alterations triggered by subtoxic concentrations of MDMA in hepatic cell 
      functions, which represents a more realistic appraisal of early toxicity events 
      posed by exposure to this drug. In addition, these results also revealed some 
      metabolites that may be used as potential biomarkers indicative of early events 
      in the hepatotoxicity induced by MDMA.
FAU - Araujo, Ana Margarida
AU  - Araujo AM
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal. 
      ana.margarida.c.araujo@gmail.com.
FAU - Bastos, Maria de Lourdes
AU  - Bastos ML
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
FAU - Fernandes, Eduarda
AU  - Fernandes E
AD  - UCIBIO, REQUIMTE, Laboratory of Applied Chemistry, Faculty of Pharmacy, 
      University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
FAU - Carvalho, Felix
AU  - Carvalho F
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
FAU - Carvalho, Marcia
AU  - Carvalho M
AUID- ORCID: 0000-0001-9884-4751
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal. 
      mcarv@ufp.edu.pt.
AD  - UFP Energy, Environment and Health Research Unit (FP-ENAS), University Fernando 
      Pessoa, Praca Nove de Abril, 349, 4249-004, Porto, Portugal. mcarv@ufp.edu.pt.
FAU - Guedes de Pinho, Paula
AU  - Guedes de Pinho P
AD  - UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of 
      Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
LA  - eng
PT  - Journal Article
DEP - 20180925
PL  - Germany
TA  - Arch Toxicol
JT  - Archives of toxicology
JID - 0417615
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Gas Chromatography-Mass Spectrometry/*methods
MH  - Hepatocytes/*drug effects/metabolism
MH  - Lipid Peroxidation/drug effects
MH  - Male
MH  - Metabolic Networks and Pathways/drug effects
MH  - *Metabolomics
MH  - Mice
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
OTO - NOTNLM
OT  - Hepatotoxicity
OT  - MDMA
OT  - Metabolomics
OT  - Primary mouse hepatocytes
OT  - Subtoxic concentrations
EDAT- 2018/09/27 06:00
MHDA- 2019/11/15 06:00
CRDT- 2018/09/27 06:00
PHST- 2018/07/01 00:00 [received]
PHST- 2018/09/19 00:00 [accepted]
PHST- 2018/09/27 06:00 [pubmed]
PHST- 2019/11/15 06:00 [medline]
PHST- 2018/09/27 06:00 [entrez]
AID - 10.1007/s00204-018-2314-9 [pii]
AID - 10.1007/s00204-018-2314-9 [doi]
PST - ppublish
SO  - Arch Toxicol. 2018 Nov;92(11):3307-3323. doi: 10.1007/s00204-018-2314-9. Epub 
      2018 Sep 25.