PMID- 12387620
OWN - NLM
STAT- MEDLINE
DCOM- 20030417
LR  - 20190922
IS  - 0893-228X (Print)
IS  - 0893-228X (Linking)
VI  - 15
IP  - 10
DP  - 2002 Oct
TI  - Inhibition of the alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase 
      complexes by a putative aberrant metabolite of serotonin, tryptamine-4,5-dione.
PG  - 1242-7
AB  - A transient energy impairment with resultant release and subsequent reuptake of 
      5-hydroxytryptamine (5-HT) and NMDA receptor activation with consequent 
      cytoplasmic superoxide (O(2)(-)(*)), nitric oxide (NO(*)), and peroxynitrite 
      (ONOO(-)) generation have all been implicated in a neurotoxic cascade which 
      ultimately leads to the degeneration of serotonergic neurons evoked by 
      methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA). Such 
      observations raise the possibility that the O(2)(-)(*)/NO(*)/ONOO(-)-mediated 
      oxidation of 5-HT, as it returns via the plasma membrane transporter to the 
      cytoplasm of serotonergic neurons when the MA/MDMA-induced energy impairment 
      begins to subside, may generate an endogenous neurotoxin. In vitro the 
      O(2)(-)(*)/NO(*)/ONOO(-)-mediated oxidation of 5-HT forms tryptamine-4,5-dione 
      (T-4,5-D). When incubated with intact rat brain mitochondria, T-4,5-D strongly 
      inhibits state 3 respiration with pyruvate or alpha-ketoglutarate as substrates 
      at concentrations which do not affect succinate-supported (complex II) 
      respiration. Experiments with freeze-thawed rat brain mitochondria reveal that 
      T-4,5-D inhibits the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase 
      complexes. These and other properties of T-4,5-D raise the possibility that it 
      may be an endogenously formed intraneuronal metabolite of 5-HT that contributes 
      to the serotonergic neurotoxicity of MA and MDMA.
FAU - Jiang, Xiang-Rong
AU  - Jiang XR
AD  - Department of Chemistry and Biochemistry, University of Oklahoma, Norman, 
      Oklahoma 73019, USA.
FAU - Dryhurst, Glenn
AU  - Dryhurst G
LA  - eng
GR  - GM32367/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Central Nervous System Stimulants)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Indolequinones)
RN  - 0 (Pyruvate Dehydrogenase Complex)
RN  - 0 (Tryptamines)
RN  - 108560-71-0 (tryptamine-4,5-dione)
RN  - 44RAL3456C (Methamphetamine)
RN  - EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Brain
MH  - Central Nervous System Stimulants/chemistry/toxicity
MH  - Enzyme Inhibitors/*pharmacology
MH  - *Indolequinones
MH  - Ketoglutarate Dehydrogenase Complex/*antagonists & inhibitors/*pharmacology
MH  - Male
MH  - Methamphetamine/chemistry/toxicity
MH  - Mitochondria
MH  - N-Methyl-3,4-methylenedioxyamphetamine/chemistry/toxicity
MH  - Pyruvate Dehydrogenase Complex/*antagonists & inhibitors/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tryptamines/*pharmacology
EDAT- 2002/10/22 04:00
MHDA- 2003/04/18 05:00
CRDT- 2002/10/22 04:00
PHST- 2002/10/22 04:00 [pubmed]
PHST- 2003/04/18 05:00 [medline]
PHST- 2002/10/22 04:00 [entrez]
AID - tx020029b [pii]
AID - 10.1021/tx020029b [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2002 Oct;15(10):1242-7. doi: 10.1021/tx020029b.