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.
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.
Nicklas
W J
WJ
Vyas
I
I
Heikkila
R E
RE
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects*; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D008293:Malates / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009243:NAD / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D005971:Glutamates; D008293:Malates; D009498:Neurotoxins; D011725:Pyridines; D009243:NAD; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; C030298:malic acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine