Aldo-Keto Reductase-7A Protects Liver Cells and Tissues From Acetaminophen-Induced Oxidative Stress and Hepatotoxicity
Aldo-Keto Reductase-7A Protects Liver Cells and Tissues From Acetaminophen-Induced Oxidative Stress and Hepatotoxicity
复制标题
醛酮还原酶 7A 保护肝细胞和组织免受对乙酰氨基酚诱导的氧化应激和肝毒性
DOI：
10.1002/hep.24493
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发表时间：
2011-10-01
期刊：
影响因子：
13.5
通讯作者：
Yang, James Y.
中科院分区：
文献类型：
--
作者：
Ahmed, Munzir M. E.;Wang, Tao;Yang, James Y.
醛酮还原酶-7A(AKR7A)是一种重要的生物活化和生物解毒酶。以前的研究表明Akr7a可能受氧化应激反应转录因子核因子2红系P45相关因子2(Nrf2)的转录调控，Nrf2是一种对对乙酰氨基酚(APAP)或其中间代谢产物N-乙酰-对苯二酚亚胺(NAPQI)高度敏感的蛋白质。因此，本研究旨在探讨Akr7a是否参与了对APAP诱导的氧化应激和肝毒性的保护作用。我们发现，作为对APAP或NAPQI暴露的响应，Akr7a3在体外显著上调了人肝癌细胞株HepG2和LO2细胞中Akr7a3的表达。同样，APAP对小鼠AML12肝细胞Akr7a5的诱导作用也很强。在野生型大鼠体内，给予APAP后，肝脏AKR7A1蛋白表达显著上调。另一方面，Nrf2的缺失降低了Akr7a3的表达，这表明Nrf2确实在Akr7a的诱导中起着重要作用。此外，AKR7A3的共表达显著挽救了NRF2缺失细胞中细胞活力的丧失。此外，HepG2细胞中AKR7A3的增加与氧化应激相关酶的上调有关，以增强细胞的抗氧化防御，这似乎对APAP诱导的毒性具有显著的保护作用。在一组过量表达AKR7A1的转基因大鼠中，增加AKR7A1刺激了Nrf2和其他Nrf2调节基因的表达，但并没有更好地保护大鼠免受APAP的伤害。相反，在体外耗尽培养的AML12细胞中Akr7a5或在体内耗尽大鼠肝脏中Akr7a1可显著增加APAP诱导的肝毒性。结论：AKR7A蛋白在APAP/NAPQI暴露后显著上调，对APAP诱导的肝毒性具有显著的保护作用。AKR7A部分地通过增强肝细胞的抗氧化防御来调节这种保护。(《肝病》2011；54：1322-1332)
Aldo-keto reductase-7A (AKR7A) is an enzyme important for bioactivation and biodetoxification. Previous studies suggested that Akr7a might be transcriptionally regulated by oxidative stress-responsive transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a protein highly responsive to acetaminophen (APAP) or its intermediate metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). This study was, therefore, carried out to investigate whether Akr7a is involved in the protection against APAP-induced oxidative stress and hepatotoxicity. We found that in response to APAP or NAPQI exposure, Akr7a3 mRNA and protein were significantly up-regulated in vitro in human HepG2 and LO2 cells. Similarly, strong induction was observed for Akr7a5 in mouse AML12 hepatocytes exposed to APAP. In vivo in wild-type rats, significant up-regulation of hepatic AKR7A1 protein was observed after administration of APAP. On the other hand, depletion of Nrf2 reduced the expression of Akr7a3, suggesting that Nrf2, indeed, contributes significantly to the induction of Akr7a. Moreover, loss of cell viability in Nrf2-depleted cells was significantly rescued by coexpression of AKR7A3. Furthermore, increased AKR7A3 in HepG2 cells was associated with the up-regulation of oxidative stress-related enzymes to enhance cellular antioxidant defense, which appeared to contribute significantly to protection against APAP-induced toxicity. In a line of transgenic rats overexpressing AKR7A1, increased AKR7A1 stimulated the expression of Nrf2 and other Nrf2-regulated genes, but did not better protect rats from APAP insults. In contrast, depletion of Akr7a5 in vitro in cultured AML12 cells or depletion of Akr7a1 in vivo in rat liver greatly increased APAP-induced hepatotoxicity. Conclusion: AKR7A proteins are significantly up-regulated in response to APAP/NAPQI exposure to contribute significantly to protection against APAP-induced hepatotoxicity. AKR7A mediates this protection, in part, through enhancing hepatocellular antioxidant defense. (HEPATOLOGY 2011;54:1322-1332)