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首页> 美国卫生研究院文献>Antioxidants >Supplemental Ascorbate Diminishes DNA Damage Yet Depletes Glutathione and Increases Acute Liver Failure in a Mouse Model of Hepatic Antioxidant System Disruption
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Supplemental Ascorbate Diminishes DNA Damage Yet Depletes Glutathione and Increases Acute Liver Failure in a Mouse Model of Hepatic Antioxidant System Disruption

机译：补充抗坏血酸剂减少DNA损伤然而抑制谷胱甘肽并在肝抗氧化系统中断的小鼠模型中增加急性肝功能衰竭

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Cellular oxidants are primarily managed by the thioredoxin reductase-1 (TrxR1)- and glutathione reductase (Gsr)-driven antioxidant systems. In mice having hepatocyte-specific co-disruption of TrxR1 and Gsr (TrxR1/Gsr-null livers), methionine catabolism sustains hepatic levels of reduced glutathione (GSH). Although most mice with TrxR1/Gsr-null livers exhibit long-term survival, ~25% die from spontaneous liver failure between 4- and 7-weeks of age. Here we tested whether liver failure was ameliorated by ascorbate supplementation. Following ascorbate, dehydroascorbate, or mock treatment, we assessed survival, liver histology, or hepatic redox markers including GSH and GSSG, redox enzyme activities, and oxidative damage markers. Unexpectedly, rather than providing protection, ascorbate (5 mg/mL, drinking water) increased the death-rate to 43%. In adults, ascorbate (4 mg/g × 3 days i.p.) caused hepatocyte necrosis and loss of hepatic GSH in TrxR1/Gsr-null livers but not in wildtype controls. Dehydroascorbate (0.3 mg/g i.p.) also depleted hepatic GSH in TrxR1/Gsr-null livers, whereas GSH levels were not significantly affected by either treatment in wildtype livers. Curiously, however, despite depleting GSH, ascorbate treatment diminished basal DNA damage and oxidative stress markers in TrxR1/Gsr-null livers. This suggests that, although ascorbate supplementation can prevent oxidative damage, it also can deplete GSH and compromise already stressed livers.
机译：细胞氧化剂主要由硫氧化辛还原酶-1（TRXR1） - 和谷胱甘肽还原酶（GSR） - 驱动的抗氧化系统进行管理。在具有肝细胞特异性特异性的小鼠的TRXR1和GSR（TRXR1 / GSR-NULL肝）的小鼠中，甲硫氨酸分解代谢维持肝脏降低的谷胱甘肽（GSH）。虽然大多数小鼠具有TRXR1 / GSR-NULL肝脏表现出长期存活，但〜25％的死于4至7周至7周之间的自发肝功能衰竭。在这里，我们测试了肝功能是否通过抗坏血酸补充而改善。抗坏血酸盐，脱氢血液或模拟治疗后，我们评估了生存，肝脏组织学或肝脏氧化还原标志物，包括GSH和GSSG，氧化还原酶活性和氧化损伤标志物。意外地，而不是提供保护，抗坏血酸（5mg / ml，饮用水）将死亡率增加到43％。在成人中，抗坏血酸（4mg / g×3天，I.P.）引起肝细胞坏死和TRXR1 / GSR-NULL肝脏中的肝GSH丧失，但不在野生型控制中。在TRXR1 / GSR-NULL肝脏中脱氢血疫液（0.3mg / g i.p.）也耗尽了肝脏GSH，而GSH水平未受野生型肝脏治疗的显着影响。然而，尽管GSH的耗尽，但抗坏血酸处理在TRXR1 / GSR-NULL肝脏中减少了基础DNA损伤和氧化应激标记物。这表明，虽然抗坏血酸物补充可以防止氧化损伤，但它也可以消耗GSH并妥协已经强调的肝脏。

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