Received for publication March 21, 2006.
Revised June 20, 2006.
Accepted for publication June 21, 2006.

A potential role for cyclized quinones derived from dopamine, DOPA and DOPAC in proteasomal inhibition

Abstract

We examined the ability of oxidation products of dopamine, DOPA and DOPAC to inhibit proteasomal activity. Dopamine DOPA and DOPAC underwent tyrosinase catalyzed oxidation to generate aminochrome, dopachrome and furanoquinone, respectively. These cyclized-quinones were then incubated with rabbit reticulocyte lysate, and proteasomal activity was measured using a fluorescently labeled peptide. The results from these studies showed that the oxidation of dopamine by tyrosinase generated product(s) that inhibited the proteasome and that proteasomal inhibition correlated with the presence of the UV/vis spectrum of aminochrome. Proteasomal inhibition by aminochrome was not prevented by the addition of SOD and catalase suggesting that reactive oxygen species were not responsible for proteasomal inhibition. which was prevented however by the addition of NADH and the quinone reductase, NQO1. Although NQO1 protected against dopamine induced proteasomal inhibition it led to greater oxygen uptake due to the generation of a redox labile hydroquinone, further emphasizing the lack of involvement of oxygen radicals in proteasomal inhibition. DOPA underwent tyrosinase catalyzed oxidation to form dopachrome, and similar to aminochrome, proteasomal inhibition correlated with the presence of a dopachrome UV/vis spectrum. The inclusion of NQO1 did not protect against proteasomal inhibition induced by dopachrome. Oxidation of DOPAC by tyrosinase generated furanoquinone which was a poor proteasome inhibitor and induced less than 20 percent inhibition at the highest concentration tested. These studies demonstrate that oxidation products including cyclized quinones derived from dopamine and related compounds rather than oxygen radicals have the ability to inhibit the proteasome. They also suggest an important protective role for NQO1 in protecting against dopamine-induced proteasomal inhibition. The ability of endogenous intermediates formed during dopaminergic metabolism to cause proteasomal inhibition provides a potential basis for the selectivity of dopaminergic neuron damage in Parkinson's disease.

Key words: Dopamine, Quinone oxidoreductase, Oxidative stress/antioxidants, Reactive intermediates

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