Department of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; Department of Pharmacy, The Third People's Hospital of Chengdu & College of Medicine, Southwest Jiaotong University, Chengdu 610031, China.
Department of Pharmacy, Sichuan Cancer Hospital & Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.
Biomed Pharmacother. 2020 Oct;130:110547. doi: 10.1016/j.biopha.2020.110547. Epub 2020 Aug 7.
Tanshinone IIA (Tan IIA), an active component in S. miltiorrhiza, has been reported to have excellent antioxidant and detoxifying activity. Here, we prove that Tan IIA attenuates acetaminophen-induced hepatotoxicity from a pharmacokinetic perspective. Compared with acetaminophen (APAP, 200 mg/kg) treated mice, Tan IIA pretreatment (30 mg/kg/d) not only reduced the plasma level of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) but also increased its bile level. After Tan IIA pretreatment, significant induction of nuclear factor E2-related factor 2 (Nrf2), multidrug resistance-associated protein 2 (Mrp2), and multidrug resistance-associated protein 4 (Mrp4) mRNA and protein expression was detected in Nrf2 mouse liver, however, much lower increase of Mrp2 and Mrp4 mRNA and protein expression was observed in Nrf2 mouse liver. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that Nrf2 bounds to antioxidant responsive elements (AREs) of the MRP2 and MRP4 promoter, thus regulating the expression of MRP2 and MRP4. in vitro experiments revealed that Tan IIA increase Nrf2, MRP2, and MRP4 expression through a mechanism of inhibiting the expression of HOX transcript antisense RNA (HOTAIR) which belongs to long non-coding RNAs. Collectively, the present results demonstrated that Tan IIA could protect against APAP-induced hepatotoxicity by altering the pharmacokinetic characteristics of APAP and its metabolites via HOTAIR-Nrf2-MRP2/4 signaling pathway, and HOTAIR plays a pivotal role in the MRP2 and MRP4 expression regulated by Nrf2.
丹参酮 IIA（Tan IIA）是丹参中的一种有效成分，具有出色的抗氧化和解毒活性。在这里，我们从药代动力学的角度证明 Tan IIA 可以减轻对乙酰氨基酚引起的肝毒性。与乙酰氨基酚（APAP，200 mg/kg）处理的小鼠相比，Tan IIA 预处理（30 mg/kg/d）不仅降低了有毒代谢物 N-乙酰苯醌亚胺（NAPQI）的血浆水平，而且还增加了其胆汁水平。Tan IIA 预处理后，在 Nrf2 小鼠肝脏中检测到核因子 E2 相关因子 2（Nrf2）、多药耐药相关蛋白 2（Mrp2）和多药耐药相关蛋白 4（Mrp4）mRNA 和蛋白表达的显著诱导，然而，在 Nrf2 小鼠肝脏中观察到 Mrp2 和 Mrp4 mRNA 和蛋白表达的增加要低得多。荧光素酶报告基因和染色质免疫沉淀分析表明，Nrf2 结合到 MRP2 和 MRP4 启动子的抗氧化反应元件（ARE）上，从而调节 MRP2 和 MRP4 的表达。体外实验表明，Tan IIA 通过抑制 HOX 转录反义 RNA（HOTAIR）的表达来增加 Nrf2、MRP2 和 MRP4 的表达，HOTAIR 属于长非编码 RNA。综上所述，这些结果表明，Tan IIA 可以通过 HOTAIR-Nrf2-MRP2/4 信号通路改变对乙酰氨基酚及其代谢物的药代动力学特征来防止 APAP 引起的肝毒性，并且 HOTAIR 在 Nrf2 调节的 MRP2 和 MRP4 表达中起关键作用。
