Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine.
The enzymes of mitochondrial respiratory chain, NADH dehydrogenase (complex I) and cytochrome c oxidase (complex IV), were completely inhibited by 6-hydroxydopamine with IC50 = 10.5 microM and IC50 = 34 microM respectively. The enzyme inhibition was insensitive to the change of NADH or cytochrome c concentrations. The extent of complex I inhibition decreased as a consequence of both non-enzymatic and monoamine oxidase-catalyzed oxidation of 6-hydroxydopamine. Monoamine oxidase A and B inhibitors, tranylcypromine and clorgyline but not l-deprenyl increased the extent of 6-hydroxydopamine induced inhibition of complex I. Thus, 6-hydroxydopamine itself and not its oxidation products may be responsible for the neurotoxicity of this agent via inhibition of respiratory chain enzymes.
Glinka
Y Y
YY
Department of Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
Youdim
M B
MB
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D008996:Monoamine Oxidase Inhibitors; D016627:Oxidopamine; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV