PMID- 24725746
OWN - NLM
STAT- MEDLINE
DCOM- 20150413
LR  - 20201209
IS  - 1873-4324 (Electronic)
IS  - 0003-2670 (Linking)
VI  - 822
DP  - 2014 Apr 25
TI  - Methylenedioxy designer drugs: mass spectrometric characterization of their 
      glutathione conjugates by means of liquid chromatography-high-resolution mass 
      spectrometry/mass spectrometry and studies on their glutathionyl transferase 
      inhibition potency.
PG  - 37-50
LID - S0003-2670(14)00320-1 [pii]
LID - 10.1016/j.aca.2014.03.017 [doi]
AB  - Methylenedioxy designer drugs of abuse such as 3,4-methylenedioxymethamphetamine 
      (MDMA) can be selectively toxic to serotonergic neurons and glutathione (GSH) 
      adducts have been implicated in its neurotoxicity. The catecholic demethylenyl 
      metabolites of MDMA, 3,4-dihydroxymethamphetamine and 3,4-dihydroxyamphetamine, 
      are metabolically oxidized to the corresponding ortho-quinones, which are highly 
      reactive intermediates. These intermediates can then be conjugated with GSH 
      preventing cellular damage. Furthermore, glutathionyl transferase (GST) activity 
      was described to be irreversibly inhibited by the catechols dopamine, 
      alpha-methyldopa and their GSH conjugates. Therefore, the aims of the present work 
      were the detection and characterization of GSH conjugates of ten methylenedioxy 
      drugs of abuse and their phase I metabolites as well as to assess their 
      inhibition potency on GST activity. The substrates were incubated using human 
      placental GST with or without preincubation by cytochrome P450 enzymes 
      preparations. GST inhibition was tested using chlorodinitrobenzene GSH 
      conjugation as marker reaction. GSH conjugates were analyzed and characterized 
      using LC-high-resolution-MS/MS. For confirmation of postulated fragmentation 
      patterns, formation of GSH conjugates of selected deuterated analogs (deuterated 
      analogue approach, DAA) of the investigated drugs was explored. For the 
      methylenedioxy amphetamines the following steps could be identified: conjugation 
      of the parent compounds at position 2, 5, 6, of the demethylenyl metabolites at 
      position 2 and 5, and of the further deaminated demethylenyl metabolites at 
      position 2. For the beta-keto-phenylalkylamine and pyrrolidinophenone, conjugation 
      of the demethylenyl metabolites and of the deaminated demethylenyl metabolites at 
      position 2 could be identified. The DAA allowed the differentiation of the 2 and 
      5/6 isomers by confirmation of the postulated mass spectral fragments. Finally, 
      the tested drugs and phase I metabolites showed no inhibition potency on GST 
      activity.
CI  - Copyright (c) 2014 Elsevier B.V. All rights reserved.
FAU - Meyer, Markus R
AU  - Meyer MR
AD  - Department of Experimental and Clinical Toxicology, Institute of Experimental and 
      Clinical Pharmacology and Toxicology, Saarland University, Homburg, Saarland, 
      Germany. Electronic address: markus.meyer@uks.eu.
FAU - Richter, Lilian H J
AU  - Richter LH
AD  - Department of Experimental and Clinical Toxicology, Institute of Experimental and 
      Clinical Pharmacology and Toxicology, Saarland University, Homburg, Saarland, 
      Germany.
FAU - Maurer, Hans H
AU  - Maurer HH
AD  - Department of Experimental and Clinical Toxicology, Institute of Experimental and 
      Clinical Pharmacology and Toxicology, Saarland University, Homburg, Saarland, 
      Germany.
LA  - eng
PT  - Journal Article
DEP - 20140320
PL  - Netherlands
TA  - Anal Chim Acta
JT  - Analytica chimica acta
JID - 0370534
RN  - 0 (Dinitrochlorobenzene)
RN  - 15398-87-5 (alpha-methylepinine)
RN  - 555-64-6 (alpha-methyldopamine)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 2.5.1.18 (Glutathione Transferase)
RN  - GAN16C9B8O (Glutathione)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - R7339QLN1C (Deoxyepinephrine)
SB  - IM
MH  - Chromatography, High Pressure Liquid
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Deoxyepinephrine/analogs & derivatives/analysis/chemistry
MH  - Dinitrochlorobenzene/chemistry
MH  - Enzyme Assays
MH  - Female
MH  - Glutathione/*chemistry
MH  - Glutathione Transferase/antagonists & inhibitors/*metabolism
MH  - Humans
MH  - Isomerism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/chemistry/*metabolism
MH  - Placenta/enzymology
MH  - Pregnancy
MH  - Spectrophotometry, Ultraviolet
MH  - Tandem Mass Spectrometry
OTO - NOTNLM
OT  - 3,4-Methylenedioxymethamphetamine
OT  - Glutathione
OT  - Glutathione conjugates
OT  - High resolution mass spectrometry
OT  - Methylenedioxy designer drugs
EDAT- 2014/04/15 06:00
MHDA- 2015/04/14 06:00
CRDT- 2014/04/15 06:00
PHST- 2014/01/25 00:00 [received]
PHST- 2014/03/07 00:00 [revised]
PHST- 2014/03/16 00:00 [accepted]
PHST- 2014/04/15 06:00 [entrez]
PHST- 2014/04/15 06:00 [pubmed]
PHST- 2015/04/14 06:00 [medline]
AID - S0003-2670(14)00320-1 [pii]
AID - 10.1016/j.aca.2014.03.017 [doi]
PST - ppublish
SO  - Anal Chim Acta. 2014 Apr 25;822:37-50. doi: 10.1016/j.aca.2014.03.017. Epub 2014 
      Mar 20.