Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
Neurotox Res. 2018 Oct;34(3):693-705. doi: 10.1007/s12640-018-9934-y. Epub 2018 Jul 28.
Sulfite oxidase, molybdenum cofactor, and ETHE1 deficiencies are autosomal recessive disorders that affect the metabolism of sulfur-containing amino acids. Patients with these disorders present severe neurological dysfunction and basal ganglia abnormalities, accompanied by high levels of thiosulfate in biological fluids and tissues. Aiming to better elucidate the pathophysiology of basal ganglia damage in these disorders, we evaluated the in vivo effects of thiosulfate administration on bioenergetics, oxidative stress, and neural damage in rat striatum. The in vitro effect of thiosulfate on creatine kinase (CK) activity was also studied. In vivo findings showed that thiosulfate administration decreased the activities of CK and citrate synthase, and increased the activity of catalase 30 min after administration. Activities of other antioxidant enzymes, citric acid cycle, and respiratory chain complex enzymes, as well as glutathione concentrations and markers of neural damage, were not altered by thiosulfate 30 min or 7 days after its administration. Thiosulfate also decreased the activity of CK in vitro in striatum of rats, which was prevented by the thiol reducing agents dithiothreitol (DTT), the antioxidants glutathione (GSH), melatonin, trolox (hydrosoluble analogue of vitamin E), and lipoic acid. DTT and GSH further prevented thiosulfate-induced decrease of the activity of a purified CK in a medium devoid of biological samples. These data suggest that thiosulfate inhibits CK activity by altering critical sulfhydryl groups of this enzyme. It may be also presumed that bioenergetics impairment and ROS generation induced by thiosulfate are mechanisms underlying the neuropathophysiology of disorders in which this metabolite accumulates.
亚硫酸盐氧化酶、钼辅因子和 ETHE1 缺乏症是影响含硫氨基酸代谢的常染色体隐性遗传病。这些疾病的患者表现出严重的神经功能障碍和基底节异常，伴有生物体液和组织中高浓度的硫代硫酸盐。为了更好地阐明这些疾病中基底节损伤的病理生理学，我们评估了硫代硫酸盐在大鼠纹状体中的体内对生物能量学、氧化应激和神经损伤的影响。还研究了硫代硫酸盐对肌酸激酶（CK）活性的体外影响。体内研究结果表明，硫代硫酸盐给药后 30 分钟可降低 CK 和柠檬酸合酶的活性，增加过氧化氢酶的活性。硫代硫酸盐给药 30 分钟或 7 天后，其他抗氧化酶、柠檬酸循环和呼吸链复合物酶的活性、谷胱甘肽浓度和神经损伤标志物均未改变。硫代硫酸盐还降低了大鼠纹状体中 CK 的体外活性，而还原剂二硫苏糖醇（DTT）、抗氧化剂谷胱甘肽（GSH）、褪黑素、trolox（维生素 E 的水溶性类似物）和硫辛酸可预防这种降低。DTT 和 GSH 还进一步预防了在缺乏生物样本的培养基中硫代硫酸盐诱导的纯化 CK 活性降低。这些数据表明，硫代硫酸盐通过改变 CK 酶的关键巯基基团来抑制 CK 活性。还可以推测，硫代硫酸盐诱导的生物能量学障碍和 ROS 生成是导致该代谢物积累的疾病神经病理生理学的机制。
