We have previously shown that inhibition of catalase and glutathione peroxidase activities in rat primary hepatocytes by 3-amino-1,2,4-triazole (ATZ) and mercaptosuccinic acid (MS) results in sustained oxidative stress, followed by apoptosis. To examine the effects of duration of oxidative stress, ATZ and MS were removed from culture medium at 3, 6 and 9 h after treatment with both inhibitors. Oxidative stress was induced for periods of time by ATZ and MS exposures in primary hepatocytes. Treatment with ATZ and MS reduced catalase (CAT) and glutathione peroxidase (GPx) activities, and decreased CAT and GPx activities recovered to normal values upon withdrawal. Although oxidative stress of up to 6 h duration did not cause cell death, sustained oxidative stress (over 9 h) induced apoptosis. The increase in the glutathione disulfide/reduced glutathione ratio under oxidative stress up to 6 h was transient and reversible, while that due to sustained oxidative stress was irreversible. These results suggest that irreversible redox shifts resulting from sustained oxidative stress play a critical role in the induction of hepatocyte apoptosis in this experimental system.

中文翻译：

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暴露时间对内源性氧化应激在肝细胞凋亡中的关键作用。

先前我们已经表明3-氨基1,2,4-三唑（ATZ）和巯基琥珀酸（MS）对大鼠原代肝细胞中过氧化氢酶和谷胱甘肽过氧化物酶活性的抑制导致持续的氧化应激，然后导致细胞凋亡。为了检查氧化应激持续时间的影响，在用两种抑制剂处理后3、6和9 h从培养基中去除了ATZ和MS。在原代肝细胞中，通过ATZ和MS暴露诱导了一段时间的氧化应激。用ATZ和MS进行治疗可降低过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GPx）的活性，并且降低的CAT和GPx活性在停药后恢复至正常值。尽管长达6小时的氧化应激不会导致细胞死亡，但是持续的氧化应激（超过9小时）会诱导细胞凋亡。在长达6小时的氧化应激下，谷胱甘肽二硫化物/还原型谷胱甘肽比率的增加是短暂且可逆的，而由于持续的氧化应激而引起的增加是不可逆的。这些结果表明，由持续的氧化应激引起的不可逆氧化还原转变在该实验系统中在诱导肝细胞凋亡中起关键作用。