Although acetaminophen (APAP) is a commonly used analgesic antipyretic drug, hepatotoxicity and nephrotoxicity are common after the overdose. The main mechanism of APAP toxicity is oxidative stress based. Stress may induce the production of heme oxygenase 1 (HO)-1 which is regulated by interleukin (IL)-10 and inhibit the production of tumor necrosis factor-alpha (TNF-α). HO-1 expression is further regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the transcription factor BTB and CNC homology 1 (BACH1). Drug-induced toxicity can be relieved by several natural products, which are preferred due to their dietary nature and less adverse reactions. Of these natural products, omega-3 (ω-3) fatty acids are known for anti-inflammatory and antioxidant actions. However, effects of ω-3fatty acids on APAP-induced hepatic and renal toxicity are not well addressed. We designed this study to test the potential protecting actions of ω-3 fatty acids (270 mg/kg Eicosapentaenoic acid and 180 mg/kg docosahexaenoic acid, orally, for 7 days) in hepatotoxicity and nephrotoxicity induced by APAP (2 g/kg, once orally on day 7) in rats. Moreover, we focused on the molecular mechanism underlying APAP hepatotoxicity and nephrotoxicity. Pre-treatment with ω-3 fatty acids enhanced liver and kidney functions indicated by decreased serum aminotransferases activities and serum creatinine and urea concentrations. These results were further confirmed by histopathological examination. Moreover, ω-3 fatty acids showed antioxidant properties confirmed by decreased malondialdehyde level and increased total antioxidant capacity. Antioxidant Nrf2, its regulators (HO-1 and BACH1) and the anti-inflammatory cytokine (IL-10) were up-regulated by APAP administration as a compensatory mechanism and they were normalized by ω-3 fatty acids. ω-3 fatty acids showed anti-inflammatory actions through down-regulating nuclear factor kappa B (NF-ĸB) and its downstream TNF-α. Moreover, Western blot analysis showed that ω-3 fatty acids promoted Nrf2 translocation to the nucleus; BACH1 exit from the nucleus and inhibited NF-ĸB nuclear translocation. These findings suggested the protecting actions of ω-3 fatty acids against APAP-induced hepatic and renal toxicity through regulation of antioxidant Nrf2 and inflammatory NF-ĸB pathways.

中文翻译：

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Omega-3脂肪酸可通过HO-1-Nrf2-BACH1途径防止对乙酰氨基酚引起的肝脏和肾脏毒性。

尽管对乙酰氨基酚（APAP）是一种常用的止痛解热药，但在用药过量后，肝毒性和肾毒性很常见。APAP毒性的主要机理是基于氧化应激。应激可能诱导血红素加氧酶1（HO）-1的产生，白细胞介素（IL）-10对其进行调节，并抑制肿瘤坏死因子-α（TNF-α）的产生。HO-1的表达进一步受到核因子红系2相关因子2（Nrf2）和转录因子BTB和CNC同源性1（BACH1）的调控。几种天然产物可以减轻药物引起的毒性，由于它们的饮食特性和较少的不良反应，因此首选天然产物。在这些天然产物中，ω-3（ω-3）脂肪酸具有抗炎和抗氧化作用。然而，ω-3脂肪酸对APAP诱导的肝肾毒性的影响尚未得到很好的解决。我们设计了这项研究，以测试ω-3脂肪酸（270 mg / kg二十碳五烯酸和180 mg / kg二十二碳六烯酸，口服，持续7天）对APAP诱导的肝毒性和肾毒性（2 g / kg，在大鼠的第7天口服一次。此外，我们集中于APAP肝毒性和肾毒性的分子机制。ω-3脂肪酸预处理可增强肝脏和肾脏功能，这可通过降低血清氨基转移酶活性以及降低血清肌酐和尿素浓度来表明。这些结果通过组织病理学检查进一步证实。此外，ω-3脂肪酸具有降低的丙二醛含量和增加的总抗氧化能力，从而证实了其抗氧化性能。抗氧化剂Nrf2，其调节剂（HO-1和BACH1）和抗炎细胞因子（IL-10）通过APAP给药被上调，作为一种补偿机制，并通过ω-3脂肪酸进行了标准化。ω-3脂肪酸通过下调核因子kappa B（NF-ĸB）及其下游TNF-α表现出抗炎作用。此外，蛋白质印迹分析表明ω-3脂肪酸促进了Nrf2易位至细胞核。BACH1从细胞核退出并抑制NF-ĸB核移位。这些发现表明，ω-3脂肪酸可通过调节抗氧化剂Nrf2和炎性NF-ĸB途径来保护APAP诱导的肝肾毒性。APAP的上调调节剂（HO-1和BACH1）和抗炎细胞因子（IL-10）作为补偿机制被上调，并被ω-3脂肪酸标准化。ω-3脂肪酸通过下调核因子kappa B（NF-ĸB）及其下游TNF-α表现出抗炎作用。此外，蛋白质印迹分析表明ω-3脂肪酸促进了Nrf2易位至细胞核。BACH1从细胞核退出并抑制NF-ĸB核移位。这些发现表明，ω-3脂肪酸可通过调节抗氧化剂Nrf2和炎性NF-ĸB途径来保护APAP诱导的肝肾毒性。APAP的上调调节剂（HO-1和BACH1）和抗炎细胞因子（IL-10）作为补偿机制被上调，并被ω-3脂肪酸标准化。ω-3脂肪酸通过下调核因子kappa B（NF-ĸB）及其下游TNF-α表现出抗炎作用。此外，蛋白质印迹分析表明ω-3脂肪酸促进了Nrf2易位至细胞核。BACH1从细胞核退出并抑制NF-ĸB核移位。这些发现表明，ω-3脂肪酸可通过调节抗氧化剂Nrf2和炎性NF-ĸB途径来保护APAP诱导的肝肾毒性。蛋白质印迹分析表明，ω-3脂肪酸促进了Nrf2易位至细胞核。BACH1从细胞核退出并抑制NF-ĸB核移位。这些发现表明，ω-3脂肪酸可通过调节抗氧化剂Nrf2和炎性NF- pathwayB途径来保护APAP诱导的肝肾毒性。蛋白质印迹分析表明，ω-3脂肪酸促进了Nrf2易位至细胞核。BACH1从细胞核退出并抑制NF-ĸB核移位。这些发现表明，ω-3脂肪酸可通过调节抗氧化剂Nrf2和炎性NF-ĸB途径来保护APAP诱导的肝肾毒性。