Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Departamento de Ciências Biológicas, Universidade Regional Integrada do Alto Uruguai e das Missões, Erechim, RS, Brazil.
Mol Neurobiol. 2018 Jul;55(7):5868-5878. doi: 10.1007/s12035-017-0804-z. Epub 2017 Nov 3.
S-Adenosylmethionine (AdoMet) concentrations are highly elevated in tissues and biological fluids of patients affected by S-adenosylhomocysteine hydrolase deficiency, who are clinically characterized by cerebral symptoms whose pathogenesis is still unknown. In the present work, we investigated the effects of AdoMet on redox homeostasis and on the activity of Na, K-ATPase in the cerebral cortex of young rats. AdoMet caused lipid peroxidation (increase of malondialdehyde concentrations) and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content). AdoMet also reduced the antioxidant defenses (reduced glutathione, GSH) and Na, K-ATPase activity. Furthermore, AdoMet-induced lipid peroxidation was fully prevented by the antioxidants trolox, melatonin, and resveratrol, and the decrease of GSH concentrations was abolished by trolox, suggesting the involvement of reactive oxygen species in these effects. In this context, AdoMet induced reactive oxygen (increase of 2',7'-dichloroflurescein-DCFH oxidation) but not nitrogen (nitrate and nitrite levels) species generation. Finally, the decrease of Na, K-ATPase activity provoked by AdoMet was totally prevented by trolox, implying a possible oxidation of cysteine groups of the enzyme that are critical for its function and highly susceptible to oxidative attack. It is also noted that adenosine and methionine did not alter the parameters evaluated, suggesting selective effects of AdoMet. Our data strongly indicate that disturbance of redox homeostasis caused by a major metabolite (AdoMet) accumulating in S-adenosylhomocysteine hydrolase deficiency may represent a deleterious mechanism of brain damage in this disease. Finally, reduction of Na, K-ATPase activity provoked by AdoMet may lead to impaired neurotransmission, but disturbance of this system should be better clarified in future studies.
S-腺苷甲硫氨酸（AdoMet）浓度在受 S-腺苷同型半胱氨酸水解酶缺乏影响的患者的组织和生物液中高度升高，这些患者的临床特征为脑症状，其发病机制尚不清楚。在本工作中，我们研究了 AdoMet 对年轻大鼠大脑皮质氧化还原平衡和 Na，K-ATP 酶活性的影响。AdoMet 导致脂质过氧化（丙二醛浓度增加）和蛋白质氧化（羰基形成增加，巯基含量减少）。AdoMet 还降低了抗氧化防御（还原型谷胱甘肽，GSH）和 Na，K-ATP 酶活性。此外，抗氧化剂 Trolox、褪黑素和白藜芦醇完全阻止了 AdoMet 诱导的脂质过氧化，而 Trolox 消除了 GSH 浓度的降低，表明活性氧参与了这些作用。在这种情况下，AdoMet 诱导了活性氧（2'，7'-二氯荧光素-DCFH 氧化增加）而不是氮（硝酸盐和亚硝酸盐水平）的产生。最后，AdoMet 引起的 Na，K-ATP 酶活性的降低被 Trolox 完全阻止，这表明酶的半胱氨酸基团可能被氧化，这些基团对其功能至关重要，并且极易受到氧化攻击。还注意到腺苷和蛋氨酸不会改变所评估的参数，这表明 AdoMet 具有选择性作用。我们的数据强烈表明，在 S-腺苷同型半胱氨酸水解酶缺乏症中积累的主要代谢物（AdoMet）引起的氧化还原平衡紊乱可能是该疾病脑损伤的一种有害机制。最后，AdoMet 引起的 Na，K-ATP 酶活性的降低可能导致神经递质传递受损，但在未来的研究中应更好地阐明该系统的紊乱。
