Dipartimento di Biologia Molecolare, Università degli Studi di Siena, via Fiorentina 1, 53100 Siena, Italy.
Rheumatology (Oxford). 2010 Oct;49(10):1975-83. doi: 10.1093/rheumatology/keq175. Epub 2010 Jul 2.
Alkaptonuria (AKU) is a rare genetic disease associated with deficient homogentisate 1,2-dioxygenase activity in the liver. This leads to the accumulation of homogentisic acid (HGA) and its oxidized/polymerized products in connective tissues, which in turn become characterized by the presence of melanin-like pigments (ochronosis). Since at present, further studies are necessary to support the use of drugs for the treatment of AKU, we investigated the effects of various anti-oxidants in counteracting melanin-like pigmentation and oxidative stress related to HGA and its metabolites.
We set up an in vitro model using human serum treated with 0.33 mM HGA and tested the anti-oxidants ascorbic acid, N-acetylcysteine, phytic acid (PHY), taurine (TAU), ferulic acid (FER) and lipoic acid (LIP) for their ability to prevent or delay the production of melanin-like pigments, as well as to reduce oxidative post-translational modifications of proteins. Monitoring of intrinsic fluorescence of HGA-induced melanin-like pigments was used to evaluate the efficacy of compounds.
Our model allowed us to prove efficacy especially for PHY, TAU, LIP and FER in counteracting the production of HGA-induced melanin-like pigments and protein oxidation induced by HGA and its metabolites.
Our model allows the opening of new anti-oxidant therapeutic strategies to treat alkaptonuric ochronosis.
尿黑酸症（AKU）是一种罕见的遗传性疾病，与肝脏中同源戊二烯 1,2-双加氧酶活性缺陷有关。这导致同型戊二酸（HGA）及其氧化/聚合产物在结缔组织中积累，进而导致黑色素样色素（褐黄病）的存在。由于目前需要进一步的研究来支持使用药物治疗 AKU，我们研究了各种抗氧化剂在对抗与 HGA 及其代谢物相关的黑色素样色素沉着和氧化应激方面的作用。
我们使用 0.33mM HGA 处理的人血清建立了体外模型，并测试了抗坏血酸、N-乙酰半胱氨酸、植酸（PHY）、牛磺酸（TAU）、阿魏酸（FER）和硫辛酸（LIP）等抗氧化剂预防或延迟黑色素样色素产生的能力，以及降低蛋白质的氧化后翻译修饰。通过监测 HGA 诱导的黑色素样色素的固有荧光来评估化合物的功效。
我们的模型证明了 PHY、TAU、LIP 和 FER 对抑制 HGA 诱导的黑色素样色素产生和 HGA 及其代谢物诱导的蛋白质氧化特别有效。
我们的模型为治疗尿黑酸症褐黄病的新抗氧化治疗策略的开辟提供了可能。
