Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization
Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization
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DOI：
10.1002/biof.5520060303
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发表时间：
1997-01-01
期刊：
影响因子：
6
通讯作者：
Packer, L
中科院分区：
文献类型：
--
作者：
Han, D;Handelman, G;Packer, L
硫辛酸（硫硫酸）被用作膳食补充剂和治疗剂，据报道，硫辛酸对氧化应激相关疾病有有益作用，但其作用机制尚不清楚。我们提供的证据表明，硫辛酸在培养的人Jurkat T细胞、人红细胞、C6胶质细胞、NB41A3神经母细胞瘤细胞和外周血淋巴细胞中诱导细胞还原性谷胱甘肽的显著增加。其作用取决于硫辛酸代谢还原为二氢硫辛酸。二氢硫辛酸被释放到培养基中，在那里它可以减少胱氨酸。由此形成的半胱氨酸很容易被中性氨基酸运输系统吸收，并用于谷胱甘肽的合成。通过这种机制，硫辛酸使胱氨酸绕过x(c)（-）运输系统，该系统在淋巴细胞中表达较弱，并被谷氨酸抑制。因此，硫辛酸使谷胱甘肽合成的关键酶γ -谷氨酰半胱氨酸合成酶在最佳条件下工作，该酶受摄取限制的半胱氨酸供应的调节。流式细胞术分析新鲜制备的人外周血淋巴细胞，使用单溴茂烷标记细胞硫醇，揭示硫辛酸主要是使硫醇状态严重受损的细胞亚群正常化，而不是使硫醇含量超过生理水平。因此，硫辛酸可能在恢复严重谷胱甘肽缺乏的细胞中具有临床意义。
Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders associated with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells, human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic reduction of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the x(c)(-) transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, gamma -glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric analysis of freshly prepared human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.