PMID- 2568404
OWN - NLM
STAT- MEDLINE
DCOM- 19890825
LR  - 20220310
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 53
IP  - 2
DP  - 1989 Aug
TI  - In vitro reactivation of rat cortical tryptophan hydroxylase following in vivo 
      inactivation by methylenedioxymethamphetamine.
PG  - 572-81
AB  - The activity of tryptophan hydroxylase (EC 1.14.16.4) from rat brain was 
      significantly decreased 1 h following a single systemic injection of 
      3,4-methylenedioxymethamphetamine (MDMA) when assessed ex vivo by radioenzymatic 
      assay or in vivo by the quantitation of 5-hydroxytryptophan accumulation 
      following central L-aromatic amino acid decarboxylase inhibition. Recovery of 
      enzymatic activity in vivo, which occurred within 24 h of low-dose MDMA 
      treatment, appeared not to involve synthesis of new enzyme protein, because the 
      return of enzymatic activity was not prevented by prior cycloheximide. Acutely 
      MDMA-depressed cortical tryptophan hydroxylase activity could be completely 
      restored in vitro by a prolonged (20-24 h) anaerobic incubation in the presence 
      of dithiothreitol and Fe2+ at 25 degrees C; partial reconstitution occurred when 
      2-mercapto-ethanol was substituted for dithiothreitol. Cortical tryptophan 
      hydroxylase acutely inactivated by methamphetamine or p-chloroamphetamine could 
      be similarly reactivated. MDMA-inactivated cortical tryptophan hydroxylase 
      derived from rats killed later than 3 days after drug treatment could not be 
      significantly reactivated under the conditions described above, indicating the 
      development of irreversible enzymatic damage. Kinetic analysis of enzyme 
      reactivation revealed an approximate doubling of enzyme Vmax with no change in 
      enzyme affinity for either substrate, tryptophan, or pterin cofactor. These 
      studies suggest that MDMA and its congeners inactivate central tryptophan 
      hydroxylase by inducing oxidation of key enzyme sulfhydryl groups. The 
      reactivation capacity of drug-inactivated enzyme at various times after MDMA 
      treatment may provide a means of assessing the development of MDMA-induced 
      neurotoxicity.
FAU - Stone, D M
AU  - Stone DM
AD  - Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 
      84112.
FAU - Hanson, G R
AU  - Hanson GR
FAU - Gibb, J W
AU  - Gibb JW
LA  - eng
GR  - DA 00869/DA/NIDA NIH HHS/United States
GR  - DA 04222/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Amphetamines)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Sulfhydryl Compounds)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - EC 1.14.16.4 (Tryptophan Hydroxylase)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/analogs & derivatives/*pharmacology
MH  - Amphetamines/*pharmacology
MH  - Animals
MH  - Cerebral Cortex/*enzymology
MH  - Enzyme Activation
MH  - Kinetics
MH  - Male
MH  - N-Methyl-3,4-methylenedioxyamphetamine
MH  - Nerve Tissue Proteins/biosynthesis
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Sulfhydryl Compounds/pharmacology
MH  - Time Factors
MH  - Tryptophan Hydroxylase/*metabolism
EDAT- 1989/08/01 00:00
MHDA- 1989/08/01 00:01
CRDT- 1989/08/01 00:00
PHST- 1989/08/01 00:00 [pubmed]
PHST- 1989/08/01 00:01 [medline]
PHST- 1989/08/01 00:00 [entrez]
AID - 10.1111/j.1471-4159.1989.tb07372.x [doi]
PST - ppublish
SO  - J Neurochem. 1989 Aug;53(2):572-81. doi: 10.1111/j.1471-4159.1989.tb07372.x.