EXOGENOUS GLUTATHIONE PROTECTS ENDOTHELIAL-CELLS FROM MENADIONE TOXICITY
EXOGENOUS GLUTATHIONE PROTECTS ENDOTHELIAL-CELLS FROM MENADIONE TOXICITY
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DOI：
10.1152/ajplung.1992.262.5.l637
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发表时间：
1992-05-01
影响因子：
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通讯作者：
FORMAN, HJ
中科院分区：
文献类型：
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作者：
CHANG, MY;MING, S;FORMAN, HJ
将美萘醌（维生素K3； 2-甲基-1,4-萘醌）给予培养的牛肺动脉内皮细胞引起细胞ATP和细胞内谷胱甘肽（GSH）的剂量和时间依赖性消耗。甲萘醌的毒性与培养基中甲萘醌-谷胱甘肽偶联物的增加和H2O2生成的增加有关。最近的研究表明谷胱甘肽可能是一种有用的药物，以防止氧化损伤。在本研究中，外源性GSH治疗可防止甲萘醌引起的细胞GSH和ATP的损失。细胞外谷胱甘肽的保护作用涉及两种机制。在一种机制中，细胞外谷胱甘肽被γ -谷氨酰转肽酶降解，为随后的细胞内从头合成谷胱甘肽产生底物。我们发现细胞外谷胱甘肽的保护作用通过抑制γ -谷氨酰转肽酶而降低。在另一种机制中，谷胱甘肽在介质中与甲萘醌反应形成共轭物。虽然细胞内甲萘醌-谷胱甘肽偶联物的形成可能导致甲萘醌毒性，但在培养基中加入甲萘醌-谷胱甘肽偶联物被发现对内皮细胞无毒。因此，外源性谷胱甘肽通过两种机制保护内皮细胞：维持细胞内谷胱甘肽和防止甲萘醌进入细胞。
Administration of menadione (vitamin K3; 2-methyl-1,4-naphthoquinone) to cultured bovine pulmonary artery endothelial cells caused a dose- and time-dependent depletion of cellular ATP and depletion of intracellular glutathione (GSH). The toxicity of menadione was correlated with an increase of menadione-glutathione conjugate in the medium and with an increase in H2O2 generation. Recent studies have suggested that GSH may be useful as a pharmacological agent to prevent oxidant injury. In the present study, treatment with exogenous GSH prevented the loss of cellular GSH and ATP caused by menadione. Protection by extracellular GSH involved two mechanisms. In one mechanism, extracellular GSH was degraded by gamma-glutamyl transpeptidase, producing substrates for subsequent intracellular de novo GSH synthesis. We found that the protective effect of extracellular GSH was decreased by inhibiting gamma-glutamyl transpeptidase. In the other mechanism, GSH reacted in the medium with menadione to form a conjugate. Although formation of the menadione-glutathione conjugate within cells may contribute to menadione toxicity, addition of menadione-glutathione conjugate to the medium was found to be nontoxic to endothelial cells. Thus exogenous GSH protected endothelial cells by two mechanisms: maintenance of intracellular GSH and prevention of menadione entrance into cells.