Inhibition of NADH oxidation by pyridine derivatives.
The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an impurity in an illicit drug, is expressed after its oxidation to 1-methyl-4-phenylpyridinium by monoamine oxidase. The pyridinium is concentrated by carrier-mediated transport into the mitochondria where it inhibits NADH dehydrogenase and, hence, ATP synthesis. Some structurally related compounds have been tested for their effect on the oxidation of NAD+-linked substrates in intact mitochondria, and for the inhibition of the accumulation of the pyridinium into mitochondria and of NADH dehydrogenase activity in a membrane preparation. Some pyridine derivatives are more inhibitory to NADH dehydrogenase than is 1-methyl-4-phenylpyridinium but these are not concentrated into mitochondria by the uptake system. 4-Phenylpyridine, one of the most effective inhibitors, both occurs naturally and is an environmental pollutant.
D015655:1-Methyl-4-phenylpyridinium; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D003579:Cytochrome Reductases / Q000037:antagonists & inhibitors*; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D007425:Intracellular Membranes / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D009243:NAD / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D005971:Glutamates; D011725:Pyridines; D011726:Pyridinium Compounds; D009243:NAD; D018698:Glutamic Acid; C051448:4-phenylpyridine; D000255:Adenosine Triphosphate; D003579:Cytochrome Reductases; D009245:NADH Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium