Glutathione metabolizing enzymes and oxidative stress in ferric nitrilotriacetate mediated hepatic injury
Glutathione metabolizing enzymes and oxidative stress in ferric nitrilotriacetate mediated hepatic injury
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DOI：
10.1080/13510002.1996.11747079
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发表时间：
1996-12-01
期刊：
影响因子：
3.8
通讯作者：
Athar, M
中科院分区：
文献类型：
--
作者：
Iqbal, M;Sharma, SD;Athar, M
谷胱甘肽（GSH）在保护细胞免受氧化损伤方面起着重要作用，特别是在暴露于异种抗生素后。硝酸三乙酸铁（Fe-NTA）是谷胱甘肽的有效消耗剂，也增强组织脂质过氧化。在本研究中，我们展示了Fe-NTA处理对肝脏GSH和一些谷胱甘肽代谢酶、氧化剂生成和肝脏损伤的影响。Fe-NTA处理后肝脏GSH水平、谷胱甘肽还原酶、谷胱甘肽s -转移酶、谷胱甘肽过氧化物酶和葡萄糖b -磷酸脱氢酶活性均降低。在这些参数中，Fe-NTA处理后12 h下降最大。相反，此时γ -谷氨酰转肽酶升高。不出所料，γ -谷氨酰转肽酶活性的增加和谷胱甘肽、谷胱甘肽过氧化物酶、谷胱甘肽还原酶、葡萄糖-磷酸脱氢酶和谷胱甘肽s -转移酶活性的降低与Fe-NTA的剂量有关。Fe-NTA也能促进H2O2的产生，增加肝脂质过氧化。与这些变化平行的是，Fe-NTA增加了肝损伤，这可以通过血清转氨酶的增加来证明。同样，肝损伤依赖于Fe-NTA的剂量，并在12小时达到最大。用抗氧化剂丁基羟基茴香醚（BHA）预处理动物，可以防止Fe-NTA介导的肝毒性，进一步支持氧化应激参与Fe-NTA介导的肝损伤。总的来说，我们的研究结果表明，Fe-NTA的施用最终导致肝脏GSH下降，谷胱甘肽代谢酶活性下降和氧化剂过量产生，所有这些都涉及导致铁介导的肝损伤的级联事件。
Glutathione (GSH) plays several important roles in the protection of cells against oxidative damage, particularly following exposure to xenobiotics. Ferric nitrilotriacetate (Fe-NTA) is a potent depletor of GSH and also enhances tissue lipid peroxidation. In this study, we show the effect of Fe-NTA treatment on hepatic GSH and some of the glutathione metabolizing enzymes, oxidant generation and liver damage. The level of hepatic GSH and the activities of glutathione reductase, glutathione S-transferase, glutathione peroxidase, and glucose B-phosphate dehydrogenase all decrease following Fe-NTA administration. In these parameters the maximum decrease occurred at 12 h following Fe-NTA treatment. In contrast, gamma-glutamyl transpeptidase was increased at this time. Not surprisingly, the increase in the activity of gamma-glutamyl transpeptidase and decreases in GSH, glutathione peroxidase, glutathione reductase, glucose g-phosphate dehydrogenase and glutathione S-transferase were found to be dependent on the dose of Fe-NTA administered. Fe-NTA administration also enhances the production of H2O2 and increases hepatic lipid peroxidation. Parallel to these changes, Fe-NTA enhances liver damage as evidenced by increases in serum transaminases. Once again, the liver damage is dependent on the dose of Fe-NTA and is maximal at 12 h. Pretreatment of animals with antioxidant, butylated hydroxy anisole (BHA), protects against Fe-NTA-mediated hepatotoxicity further supporting the involvement of oxidative stress in Fe-NTA-mediated hepatic damage. In aggregate, our results indicate that Fe-NTA administration eventuates in decreased hepatic GSH, a fall in the activities of glutathione metabolizing enzymes and excessive production of oxidants, all of which are involved in the cascade of events leading to iron-mediated hepatic injury.