One-electron oxidation of catecholamines generates free radicals with an in vitro toxicity correlating with their lifetime.
One-electron oxidation of dopamine by ferricyanide generates a highly reactive free radical intermediate that inactivates the V-type H(+)-ATPase proton pump in catecholamine storage vesicles, i.e., the driving force in both the vesicular uptake and the storage of catecholamines, in a cell-free in vitro model system at pH 7.0. Electron paramagnetic resonance spectroscopy revealed that a radical with g=2.0045, formed by this oxidation, was relatively long-lived (t(1/2) obs=79 s at pH 6.5 and 25 degrees C). Experimental evidence is presented that the observed radical most likely represents dopamine semiquinone free radical, although an o-quinone free radical cannot be ruled out. Oxidation of noradrenaline and adrenaline by ferricyanide generated similar isotropic radicals, but of shorter half-lives (i.e., 43 and 5.3 s, respectively), and the efficacy of inactivation of the H(+)-ATPase correlated with the half-life of the respective catecholamine free radical (i.e., dopamine >noradrenaline>>adrenaline). Thus, the generation of relatively long-lived semiquinone free radicals, although at low concentrations, in dopaminergic and noradrenergic neurons may represent a common mechanism of cytotoxicity linked to neurodegeneration of the respective neurons related to Parkinson disease.
Terland
Ole
O
Department of Biomedicine, Section for Biochemistry and Molecular Biology, University of Bergen, Jonas Lies Vei 91, N-5009 Bergen, Norway.
Almås
Bjørg
B
Flatmark
Torgeir
T
Andersson
K Kristoffer
KK
Sørlie
Morten
M
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D002395:Catecholamines / Q000378:metabolism* / Q000633:toxicity; D002417:Cattle; D002837:Chromaffin Granules / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity; D004583:Electrons; D004837:Epinephrine / Q000378:metabolism / Q000633:toxicity; D005292:Ferricyanides / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism / Q000633:toxicity; D066298:In Vitro Techniques; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction
D002395:Catecholamines; D005292:Ferricyanides; D005609:Free Radicals; C007931:hexacyanoferrate III; D000251:Adenosine Triphosphatases; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine