Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine

Life Sci. 1985 Jul 1;36(26):2503-8. doi: 10.1016/0024-3205(85)90146-8.

Abstract

1-methyl-4-phenylpyridine (MPP+), a major metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) inhibited the ADP-stimulated and uncoupled oxidation of NADH-linked substrates by brain mitochondrial preparations. MPTP itself was ineffective. The apparent Ki's for MPP+ inhibition of pyruvate or glutamate oxidation by purified rat brain mitochondria were approximately 300 and 400 microM, respectively; with mouse brain mitochondria the values were lower, 60 and 150 microM, respectively. Succinate oxidation was unaffected by either compound. Compromise of mitochondrial oxidative capacity by MPP+ could be an important factor in mechanisms underlying the toxicity of MPTP.

Publication types

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

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Adenosine Diphosphate / pharmacology
  • Animals
  • Brain / drug effects*
  • Glutamates / metabolism
  • Glutamic Acid
  • Malates / metabolism
  • Male
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • NAD / antagonists & inhibitors*
  • NAD / metabolism
  • Neurotoxins / metabolism*
  • Oxidation-Reduction / drug effects
  • Phosphorylation
  • Pyridines / metabolism*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Inbred Strains

Substances

  • Glutamates
  • Malates
  • Neurotoxins
  • Pyridines
  • NAD
  • Glutamic Acid
  • Adenosine Diphosphate
  • malic acid
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine