GLUTATHIONE DEFICIENCY DECREASES TISSUE ASCORBATE LEVELS IN NEWBORN RATS - ASCORBATE SPARES GLUTATHIONE AND PROTECTS
GLUTATHIONE DEFICIENCY DECREASES TISSUE ASCORBATE LEVELS IN NEWBORN RATS - ASCORBATE SPARES GLUTATHIONE AND PROTECTS
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DOI：
10.1073/pnas.88.11.4656
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发表时间：
1991-06-01
影响因子：
11.1
通讯作者：
MEISTER, A
中科院分区：
文献类型：
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作者：
MRTENSSON, J;MEISTER, A
新生大鼠的谷胱甘肽缺乏症是由给予L-丁硫氨酸-(S，R)-亚磺胺造成的，后者是一种γ-谷氨酰半胱氨酸合成酶的过渡态失活剂，可降低肾、肝、脑和肺的抗坏血酸水平。这些组织，特别是它们的线粒体受到严重破坏，动物在几天内死亡。当谷胱甘肽水平显著降低时，抗坏血酸水平下降，导致脱氢抗坏血酸的形成，而脱氢抗坏血酸被降解。抗坏血酸具有很高的抗氧化活性，但它(以及其他抗氧化剂，如α-生育酚)必须以较低的形式保持。这些研究表明，在体内，谷胱甘肽的一个重要功能是维持组织中的抗坏血酸。大剂量的抗坏血酸(但不是脱氢抗坏血酸)给丁硫氨酸亚磺胺处理的新生大鼠降低死亡率，导致抗坏血酸和谷胱甘肽的正常水平。给予低剂量丁硫氨酸亚磺胺的新生大鼠会发生白内障，如前所述，可以通过给予谷胱甘肽单酯来预防；正如这里所发现的，这种白内障可以通过给予高剂量的抗坏血酸或脱氢抗坏血酸来部分预防。抗坏血酸不含谷胱甘肽，表明这些化合物具有相似的抗氧化作用。抗坏血酸可能具有谷胱甘肽不能有效执行的还原功能。虽然谷胱甘肽通常起到维持抗坏血酸、α-生育酚和其他细胞成分处于还原状态的作用，但在严重谷胱甘肽缺乏的情况下，抗坏血酸可以作为一种基本的抗氧化剂。
Glutathione deficiency in newborn rats, produced by administration of L-buthionine-(S,R)-sulfoximine, a transition-state inactivator of gamma-glutamylcysteine synthetase, decreases ascorbate levels of kidney, liver, brain, and lung. These tissues, especially their mitochondria, undergo severe damage and the animals die within a few days. When glutathione levels are markedly decreased, ascorbate levels decrease leading to formation of dehydroascorbate, which is degraded. Ascorbate has high antioxidant activity, but it (and other antioxidants such as alpha-tocopherol) must be maintained in reduced forms. These studies show in vivo that an important function of glutathione is to maintain tissue ascorbate. Administration of large doses of ascorbate (but not of dehydroascorbate) to buthionine sulfoximine-treated newborn rats decreases mortality, leads to normal levels of ascorbate, and spares glutathione. Newborn rats given lower doses of buthionine sulfoximine develop cataracts that, as shown previously, can be prevented by giving glutathione monoester; as found here, such cataracts can be partially prevented by administration of high doses of ascorbate or dehydroascorbate. Ascorbate spares glutathione indicating that these compounds have similar antioxidant actions. Ascorbate may have reductive functions that are not efficiently performed by glutathione. Although glutathione normally functions to maintain ascorbate, alpha-tocopherol, and other cellular components in reduced states, ascorbate can serve as an essential antioxidant in the presence of severe glutathione deficiency.