Laboratório de Bioenergética e Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil.
Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil.
Mol Cell Biochem. 2017 Nov;435(1-2):207-214. doi: 10.1007/s11010-017-3070-5. Epub 2017 May 25.
Tyrosine levels are abnormally elevated in tissues and body fluids of patients with inborn errors of tyrosine metabolism. Tyrosinemia type II, which is caused by tyrosine aminotransferase deficiency, provokes eyes, skin, and central nervous system disturbances in affected patients. However, the mechanisms of brain damage are still poorly known. Considering that studies have demonstrated that oxidative stress may contribute, along with other mechanisms, to the neurological dysfunction characteristic of hypertyrosinemia, in the present study we investigated the effects of antioxidant treatment (NAC and DFX) on DNA damage and oxidative stress markers induced by chronic administration of L-tyrosine in cerebral cortex, hippocampus, and striatum of rats. The results showed elevated levels of DNA migration, and thus DNA damage, after chronic administration of L-tyrosine in all the analyzed brain areas, and that the antioxidant treatment was able to prevent DNA damage in cerebral cortex and hippocampus. However, the co-administration of NAC plus DFX did not prevent the DNA damage in the striatum. Moreover, we found a significant increase in thiobarbituric acid-reactive substances (TBA-RS) and DCFH oxidation in cerebral cortex, as well as an increase in nitrate/nitrite levels in the hippocampus and striatum. Additionally, the antioxidant treatment was able to prevent the increase in TBA-RS levels and in nitrate/nitrite levels, but not the DCFH oxidation. In conclusion, our findings suggest that reactive oxygen and nitrogen species and oxidative stress can play a role in DNA damage in this disorder. Moreover, NAC/DFX supplementation to tyrosinemia type II patients may represent a new therapeutic approach and a possible adjuvant to the current treatment of this disease.
在先天性酪氨酸代谢错误的患者的组织和体液中，酪氨酸水平异常升高。由于酪氨酸氨基转移酶缺乏引起的酪氨酸血症 II 型会引起受影响患者的眼睛、皮肤和中枢神经系统紊乱。然而，脑损伤的机制仍知之甚少。考虑到研究表明，氧化应激可能与其他机制一起导致高酪氨酸血症的神经功能障碍，本研究我们研究了抗氧化治疗（NAC 和 DFX）对慢性 L-酪氨酸给药在大鼠大脑皮质、海马体和纹状体中诱导的 DNA 损伤和氧化应激标志物的影响。结果表明，在所有分析的脑区中，慢性 L-酪氨酸给药后 DNA 迁移水平升高，即 DNA 损伤，抗氧化治疗能够预防大脑皮质和海马体的 DNA 损伤。然而，NAC 加 DFX 的联合给药不能防止纹状体中的 DNA 损伤。此外，我们发现大脑皮质中的硫代巴比妥酸反应物质（TBA-RS）和 DCFH 氧化显著增加，以及海马体和纹状体中的硝酸盐/亚硝酸盐水平增加。此外，抗氧化治疗能够预防 TBA-RS 水平和硝酸盐/亚硝酸盐水平的增加，但不能预防 DCFH 氧化。总之，我们的研究结果表明，活性氧和氮物种以及氧化应激可能在该疾病的 DNA 损伤中起作用。此外，NAC/DFX 补充酪氨酸血症 II 型患者可能代表该疾病当前治疗的一种新的治疗方法和可能的辅助方法。
