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首页> 外文期刊>Biochemical and Biophysical Research Communications >Omeprazole induces NAD(P)H quinone oxidoreductase 1 via aryl hydrocarbon receptor-independent mechanisms: Role of the transcription factor nuclear factor erythroid 2-related factor 2
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Omeprazole induces NAD(P)H quinone oxidoreductase 1 via aryl hydrocarbon receptor-independent mechanisms: Role of the transcription factor nuclear factor erythroid 2-related factor 2

机译：奥美拉唑通过不依赖芳基烃受体的机制诱导NAD（P）H醌氧化还原酶1：转录因子核因子红系2相关因子2的作用

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摘要

Activation of the aryl hydrocarbon receptor (AhR) transcriptionally induces phase I (cytochrome P450 (CYP) 1A1) and phase II (NAD(P)H quinone oxidoreductase 1 (NQO1) detoxifying enzymes. The effects of the classical and nonclassical AhR ligands on phase I and II enzymes are well studied in human hepatocytes. Additionally, we observed that the proton pump inhibitor, omeprazole (OM), transcriptionally induces CYP1A1 in the human adenocarcinoma cell line, H441 cells via AhR. Whether OM activates AhR and induces the phase II enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1), in fetal primary human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce NQO1 in HPMEC via the AhR. The concentrations of OM used in our experiments did not result in cytotoxicity. OM activated AhR as evident by increased CYP1A1 mRNA expression. However, contrary to our hypothesis, OM increased NQO1 mRNA and protein via an AhR-independent mechanism as AhR knockdown failed to abrogate OM-mediated increase in NQO1 expression. Interestingly, OM activated Nrf2 as evident by increased phosphoNrf2 (S40) expression in OM-treated compared to vehicle-treated cells. Furthermore, Nrf2 knockdown abrogated OM-mediated increase in NQO1 expression. In conclusion, we provide evidence that OM induces NQO1 via AhR-independent, but Nrf2-dependent mechanisms. (C) 2015 Elsevier Inc. All rights reserved.
机译：芳烃受体（AhR）的转录激活诱导I期（细胞色素P450（CYP）1A1）和II期（NAD（P）H醌氧化还原酶1（NQO1）解毒酶。经典和非经典AhR配体对相的影响I和II酶在人肝细胞中得到了很好的研究，此外，我们观察到质子泵抑制剂奥美拉唑（OM）通过AhR在人腺癌细胞H441细胞中转录诱导CYP1A1，OM是否激活AhR并诱导II期胎儿原代人肺微血管内皮细胞（HPMEC）中的NAD（P）H醌氧化还原酶1（NQO1）酶是未知的，因此，我们检验了OM通过AhR诱导HPMEC中NQO1的假说。在我们的实验中并未导致细胞毒性，通过CYP1A1 mRNA表达的增加，OM激活了AhR;但是，与我们的假设相反，OM通过不依赖AhR的机制增加了NQO1 mRNA和蛋白质，如Ah R组合式无法消除OM介导的NQO1表达增加。有趣的是，OM处理后的OM激活了Nrf2，这与用媒介物处理过的细胞相比，通过OM处理的phosphoNrf2（S40）表达增加而明显。此外，Nrf2敲低废除了OM介导的NQO1表达增加。总之，我们提供了证据表明OM通过独立于AhR但依赖Nrf2的机制诱导NQO1。 （C）2015 Elsevier Inc.保留所有权利。

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