1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline, a new inhibitor of complex I.
The neurotoxic agent MPP+ is an artificial substance producing a syndrome very similar to that of idiopathic Parkinson's disease. There are also naturally occuring neurotoxic substances under discussion like the group of isoquinoline and beta-carboline alkaloids. All these substances are more or less powerfull inhibitors of complex I of the mitochondrial oxidative phosphorylation. This study examined the effect of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a putative in vivo condensation product of chloralhydrate and tryptamine, on the oxidative phosphorylation system compared to MPP+. Similar to MPP+, TaClo inhibits only the electron transfer from complex I towards ubiquinone. Demonstrating a 10-times more effective inhibition than MPP+, complex I activity is fully inhibited by 800 microM TaClo in brain homogenates and submitochondrial particles. By extending the preincubation time from 5 to 30 min complex I is already inhibited by 400 microM TaClo. Other derivates of TaClo as N-methyl-TaClo demonstrate an even greater inhibitory effect on complex I and especially on complex II activities.
Janetzky
B
B
Department of Neurology, University of Würzburg, Federal Republic of Germany.
God
R
R
Bringmann
G
G
Reichmann
H
H
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers; D002243:Carbolines / Q000633:toxicity*; D003593:Cytoplasm / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D009498:Neurotoxins / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
D015415:Biomarkers; D002243:Carbolines; D004791:Enzyme Inhibitors; D009498:Neurotoxins; C067372:1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline; D016660:NAD(P)H Dehydrogenase (Quinone); D015655:1-Methyl-4-phenylpyridinium