PMID- 21795466
OWN - NLM
STAT- MEDLINE
DCOM- 20120502
LR  - 20131121
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 39
IP  - 11
DP  - 2011 Nov
TI  - Investigation on the enantioselectivity of the sulfation of the 
      methylenedioxymethamphetamine metabolites 3,4-dihydroxymethamphetamine and 
      4-hydroxy-3-methoxymethamphetamine using the substrate-depletion approach.
PG  - 1998-2002
LID - 10.1124/dmd.111.041129 [doi]
AB  - Different pharmacokinetic properties are known for the two enantiomers of the 
      entactogen 3,4-methylendioxy-methamphetamine (MDMA), most likely due to 
      enantioselective metabolism. The aim of the present work was 1) the investigation 
      of the main sulfotransferases (SULT) isoenzymes involved in the sulfation of the 
      main MDMA phase I metabolites 3,4-dihydroxymethamphetamine (DHMA) and 
      4-hydroxy-3-methoxymethamphetamine (HMMA) and 2) the evaluation of a possible 
      enantioselectivity of this phase II metabolic step. Therefore, racemic DHMA and 
      HMMA were incubated with heterologously expressed SULTs, and quantification of 
      the sulfates by liquid chromatography-high-resolution mass spectrometry was 
      conducted. Because separation of DHMA and HMMA sulfate could not be achieved by 
      liquid chromatography, enantioselective kinetic parameters were determined using 
      the substrate-depletion approach with enantioselective quantification of 
      substrate consumption by gas chromatography-negative ion chemical ionization mass 
      spectrometry. SULT1A1 and SULT1A3 catalyzed sulfation of DHMA, and SULT1A3 and 
      SULT1E1 catalyzed sulfation of HMMA. SULT1A1 and SULT1E1 revealed classic 
      Michaelis-Menten kinetics, whereas SULT1A3 kinetics showed deviation from the 
      typical Michaelis-Menten kinetics, resulting in a concentration-dependent 
      self-inhibition. SULT1A3 showed the highest affinity and capacity of the SULT 
      isoforms. Marked enantioselectivity could be observed for S-DHMA sulfation by 
      SULT1A3 and in human liver cytosol, whereas no differences were observed for HMMA 
      sulfation. Finally, comparison of K(m) and V(max) values calculated using achiral 
      product formation and chiral substrate depletion showed good correlation within 
      2-fold of each other. In conclusion, preferences for S-enantiomers were observed 
      for DHMA sulfation, but not for HMMA sulfation.
FAU - Schwaninger, Andrea E
AU  - Schwaninger AE
AD  - Department of Experimental and Clinical Toxicology, Institute of Experimental and 
      Clinical Pharmacology and Toxicology, Saarland University, Building 46, D-66421 
      Homburg (Saar), Germany.
FAU - Meyer, Markus R
AU  - Meyer MR
FAU - Maurer, Hans H
AU  - Maurer HH
LA  - eng
PT  - Journal Article
DEP - 20110727
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Isoenzymes)
RN  - 0 (Lactates)
RN  - 0 (Mandelic Acids)
RN  - 0 (Sulfates)
RN  - 117652-28-5 (4-hydroxy-3-methoxymethamphetamine)
RN  - 44RAL3456C (Methamphetamine)
RN  - 515-30-0 (atrolactic acid)
RN  - 775-01-9 (3,4-dihydroxymandelic acid)
RN  - EC 2.8.2.- (Sulfotransferases)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Chromatography, Gas/methods
MH  - Chromatography, Liquid/methods
MH  - Humans
MH  - Isoenzymes/metabolism
MH  - Kinetics
MH  - Lactates/chemistry/metabolism
MH  - Mandelic Acids/chemistry/metabolism
MH  - Mass Spectrometry/methods
MH  - Metabolic Detoxication, Phase I
MH  - Metabolic Detoxication, Phase II
MH  - Methamphetamine/*analogs & derivatives/chemistry/metabolism
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*chemistry/*metabolism
MH  - Sulfates/*metabolism
MH  - Sulfotransferases/*metabolism
EDAT- 2011/07/29 06:00
MHDA- 2012/05/04 06:00
CRDT- 2011/07/29 06:00
PHST- 2011/07/29 06:00 [entrez]
PHST- 2011/07/29 06:00 [pubmed]
PHST- 2012/05/04 06:00 [medline]
AID - dmd.111.041129 [pii]
AID - 10.1124/dmd.111.041129 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2011 Nov;39(11):1998-2002. doi: 10.1124/dmd.111.041129. Epub 
      2011 Jul 27.