Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs
Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs
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DOI：
10.2174/1389200216666151015114515
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发表时间：
2015-01-01
影响因子：
2.3
通讯作者：
Fujii, Junichi
中科院分区：
文献类型：
--
作者：
Homma, Takujiro;Fujii, Junichi
谷胱甘肽（GSH）是一种丰富的三肽分子，在保护细胞免受氧化应激诱导的细胞损伤以及解毒外源性物质和药物代谢中起着关键作用。GSH现在正进入治疗应用的新时代。GSH水平降低与衰老的共同特征以及广泛的病理状况（包括神经退行性疾病）相关。值得注意的是，GSH消耗和/或其代谢的改变似乎在帕金森病的发病中至关重要。尽管GSH是细胞存活所必需的，但将GSH耗竭与细胞死亡联系起来的分子机制仍然知之甚少。最近，相当多的注意力已经集中在一个新定义的细胞死亡类型：铁依赖性细胞死亡，也被称为“ferroptosis”。铁螯合剂去铁胺几乎消除了通过抑制GSH合成或xCT转运蛋白摄取胱氨酸诱导的铁凋亡。去铁胺优先消除溶酶体内铁的积累，并抑制氧化应激诱导的溶酶体膜透化和细胞死亡。GSH和由其衍生的前药的使用可以是有用的，因为GSH氧化还原系统的功能障碍似乎引起多种疾病，包括神经退行性疾病。然而，GSH作为治疗剂的有效性是有限的，因为其生物利用度低。我们还审查了旨在科普这一困难的试验;例如，使用前体如N-乙酰半胱氨酸和化学修饰如甲基化。
Glutathione (GSH), an abundant tripeptidyl molecule, plays pivotal roles in protecting cells against oxidative stress-induced cellular damage and in detoxifying xenobiotics and drug metabolism. GSH is now entering a new era of therapeutic applications. Decreased GSH levels are associated with the common features of aging as well as of a wide range of pathological conditions, including neurodegenerative disorders. Notably, GSH depletion and/or alterations in its metabolism appear to be crucial in the onset of Parkinson's disease. Despite the fact that GSH is required for cell survival, the molecular mechanism that links GSH depletion to cell death remains poorly understood. Recently, considerable attention has been focused on a newly defined type of cell death: iron-dependent cell death, also referred to as "ferroptosis". The iron chelator deferoxamine nearly abolishes ferroptosis induced by inhibiting GSH synthesis or cystine uptake by the xCT transporter. Deferoxamine preferentially abrogates the intralysosomal accumulation of iron and inhibits oxidative stress-induced lysosomal membrane permeabilization and cell death. The use of GSH and a prodrug derived from it can be useful, since the dysfunction of the GSH redox system appears to cause a variety of diseases including neurodegenerative disorders. However, the effectiveness of GSH as a therapeutic agent is limited because of its low bioavailability. We also review trials that have been designed to cope with this difficulty; e.g. the use of precursors such as N-acetyl cysteine and chemical modification such as methylation.