Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism.
4-Phenyl-N-methylpyridinium (MPP+), the oxidation product of the neurotoxic amine MPTP, is considerably more inhibitory to the oxidation of NAD+-linked substrates in intact mitochondria in State 3 than is 4-phenylpyridine. On adding uncouplers, the inhibition by MPP+ progressively diminishes, while the effect of 4-phenylpyridine remains. This is in accord with the fact that MPP+ is rapidly concentrated in the mitochondria by an energy-dependent process, while 4-phenylpyridine seems to enter passively with the concentration gradient. Collapse of the electrical gradient after addition of uncouplers thus leaves the inhibition by 4-phenylpyridine unaffected but causes efflux of MPP+ from the mitochondria and a reversal of its inhibitory action. In isolated inner membranes the inhibition of NADH oxidation via the respiratory chain by 4-phenylpyridine is much greater than by MPP+. MPTP and 4-phenyl-N-methylpyridinone also inhibit more than MPP+, whereas N-methylpyridinium has relatively little effect. The block is not at the point of entry of electrons into the flavoprotein since the NADH-ferricyanide activity is not inhibited by MPP+ at Vmax.
D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D002417:Cattle; D002470:Cell Survival; D003342:Corpus Striatum / Q000166:cytology; D003579:Cytochrome Reductases / Q000037:antagonists & inhibitors*; D004579:Electron Transport / Q000187:drug effects; D007425:Intracellular Membranes / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology*; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects; D010300:Parkinson Disease / Q000201:enzymology*; D011726:Pyridinium Compounds / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013378:Substantia Nigra / Q000166:cytology
D011726:Pyridinium Compounds; D003579:Cytochrome Reductases; D009245:NADH Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium