Inhibition of the alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes by a putative aberrant metabolite of serotonin, tryptamine-4,5-dione

Chem Res Toxicol. 2002 Oct;15(10):1242-7. doi: 10.1021/tx020029b.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain
  • Central Nervous System Stimulants / chemistry
  • Central Nervous System Stimulants / toxicity
  • Enzyme Inhibitors / pharmacology*
  • Indolequinones*
  • Ketoglutarate Dehydrogenase Complex / antagonists & inhibitors*
  • Ketoglutarate Dehydrogenase Complex / pharmacology*
  • Male
  • Methamphetamine / chemistry
  • Methamphetamine / toxicity
  • Mitochondria
  • N-Methyl-3,4-methylenedioxyamphetamine / chemistry
  • N-Methyl-3,4-methylenedioxyamphetamine / toxicity
  • Pyruvate Dehydrogenase Complex / antagonists & inhibitors*
  • Pyruvate Dehydrogenase Complex / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Tryptamines / pharmacology*


  • Central Nervous System Stimulants
  • Enzyme Inhibitors
  • Indolequinones
  • Pyruvate Dehydrogenase Complex
  • Tryptamines
  • tryptamine-4,5-dione
  • Methamphetamine
  • Ketoglutarate Dehydrogenase Complex
  • N-Methyl-3,4-methylenedioxyamphetamine