Dos Santos Mello Mariana, Ribas Graziela Schmitt, Wayhs Carlos Alberto Yasin, Hammerschmidt Tatiane, Guerreiro Gilian Batista Balbueno, Favenzani Jéssica Lamberty, Sitta Ângela, de Moura Coelho Daniella, Wajner Moacir, Vargas Carmen Regla
Programa de Pós-Graduação Ciências Farmacêuticas da Universidade Federal do Rio Grande do Sul (UFRGS), Ipiranga 2752, Porto Alegre, RS, 90610-000, Brazil,
Mol Cell Biochem. 2015 Apr;402(1-2):149-55. doi: 10.1007/s11010-014-2322-x. Epub 2015 Jan 4.
3-hydroxy-3-methylglutaric aciduria (HMGA; OMIM 246450) is a rare autosomal recessive disorder, caused by the deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (4.1.3.4), which results in the accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Recent in vivo and in vitro animal studies have demonstrated that the accumulation of these metabolites can disturb the cellular redox homeostasis, which can contribute to the neurological manifestations presented by the patients. So, in the present work, we investigated oxidative stress parameters in plasma and urine samples from HMGA patients, obtained at the moment of diagnosis of this disorder and during therapy with low-protein diet and L-carnitine supplementation. It was verified that untreated HMGA patients presented higher levels of urinary di-tyrosine and plasma thiobarbituric acid-reactive substances (TBA-RS), which are markers of protein and lipid oxidative damage, respectively, as well as a reduction of the urinary antioxidant capacity. Treated HMGA patients also presented an increased protein oxidative damage, as demonstrated by their higher concentrations of plasma protein carbonyl groups and urinary di-tyrosine, as well as by the reduction of total sulfhydryl groups in plasma, in relation to controls. On the other hand, HMGA patients under therapy presented normal levels of TBA-RS and urinary antioxidant capacity, which can be related, at least in part, to the antioxidant and antiperoxidative effects exerted by L-carnitine. The results of this work are the first report showing that a redox imbalance occurs in patients with HMGA what reinforces the importance of the antioxidant therapy in this disorder.
3-羟基-3-甲基戊二酸尿症（HMGA；OMIM 246450）是一种罕见的常染色体隐性疾病，由3-羟基-3-甲基戊二酰辅酶A裂解酶（4.1.3.4）缺乏引起，导致3-羟基-3-甲基戊二酸（HMG）和3-甲基戊二酸（MGA）在受影响个体的组织和生物体液中蓄积。最近的体内和体外动物研究表明，这些代谢产物的蓄积会扰乱细胞氧化还原稳态，这可能导致患者出现神经学表现。因此，在本研究中，我们调查了HMGA患者在该疾病诊断时以及低蛋白饮食和补充L-肉碱治疗期间采集的血浆和尿液样本中的氧化应激参数。结果证实，未经治疗的HMGA患者尿中二酪氨酸和血浆硫代巴比妥酸反应性物质（TBA-RS）水平较高，它们分别是蛋白质和脂质氧化损伤的标志物，同时尿抗氧化能力降低。与对照组相比，接受治疗的HMGA患者也表现出蛋白质氧化损伤增加，表现为血浆蛋白羰基和尿中二酪氨酸浓度升高，以及血浆中总巯基减少。另一方面，接受治疗的HMGA患者TBA-RS和尿抗氧化能力水平正常，这至少部分与L-肉碱发挥的抗氧化和抗过氧化作用有关。本研究结果首次表明HMGA患者存在氧化还原失衡，这进一步强调了抗氧化治疗在该疾病中的重要性。
