Zafar Khan Shoeb, Siegel David, Ross David
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA.
Mol Pharmacol. 2006 Sep;70(3):1079-86. doi: 10.1124/mol.106.024703. Epub 2006 Jun 21.
We examined the ability of oxidation products of dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid (DOPAC) to inhibit proteasomal activity. Dopamine, DOPA, and DOPAC underwent tyrosinase-catalyzed oxidation to generate aminochrome, dopachrome, and furanoquinone, respectively. In these studies, the oxidation of dopamine by tyrosinase generated product(s) that inhibited the proteasome, and proteasomal inhibition correlated with the presence of the UV-visible spectrum of aminochrome. The addition of superoxide dismutase and catalase did not prevent proteasomal inhibition. The addition of NADH and the quinone reductase NAD(P)H:quinone oxidoreductase 1 (NQO1) protected against aminochrome-induced proteasome inhibition. Although NQO1 protected against dopamine-induced proteasomal inhibition, the metabolism of aminochrome by NQO1 led to oxygen uptake because of the generation of a redox-labile cyclized hydroquinone, further demonstrating 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-visible 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. 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.
我们研究了多巴胺、多巴（DOPA）和3,4-二羟基苯乙酸（DOPAC）的氧化产物抑制蛋白酶体活性的能力。多巴胺、多巴和DOPAC分别经酪氨酸酶催化氧化生成氨基色素、多巴色素和呋喃醌。在这些研究中，酪氨酸酶催化多巴胺氧化生成的产物能抑制蛋白酶体，蛋白酶体抑制作用与氨基色素紫外-可见光谱的存在相关。添加超氧化物歧化酶和过氧化氢酶并不能防止蛋白酶体抑制。添加烟酰胺腺嘌呤二核苷酸（NADH）和醌还原酶NAD(P)H:醌氧化还原酶1（NQO1）可防止氨基色素诱导的蛋白酶体抑制。虽然NQO1可防止多巴胺诱导的蛋白酶体抑制，但NQO1对氨基色素的代谢会因生成氧化还原不稳定的环化对苯二酚而导致氧气摄取，进一步证明氧自由基不参与蛋白酶体抑制。多巴经酪氨酸酶催化氧化形成多巴色素，与氨基色素类似，蛋白酶体抑制作用与多巴色素紫外-可见光谱的存在相关。加入NQO1并不能防止多巴色素诱导的蛋白酶体抑制。酪氨酸酶催化DOPAC氧化生成呋喃醌，它是一种较弱的蛋白酶体抑制剂。这些研究表明，包括源自多巴胺及相关化合物的环化醌在内的氧化产物而非氧自由基具有抑制蛋白酶体的能力。它们还表明NQO1在防止多巴胺诱导的蛋白酶体抑制方面具有重要的保护作用。多巴胺能代谢过程中形成的内源性中间体导致蛋白酶体抑制的能力为帕金森病中多巴胺能神经元损伤的选择性提供了潜在基础。
