Tanshinone IIA attenuates acetaminophen-induced hepatotoxicity through HOTAIR-Nrf2-MRP2/4 signaling pathway - 27/10/20
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Graphical abstract |
Highlights |
• | Nrf2-MRP2/4 pathway is essential for Tan IIA to prevent APAP-induced hepatotoxicity. |
• | Nrf2 directly regulates MRP2/4 via binding to AREs in their promoters. |
• | HOTAIR performs an epigenetic suppression on Nrf2-MRP2/4 pathway. |
• | Tan IIA activates Nrf2-MRP2/4 pathway via downregulating HOTAIR. |
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Abbreviations : Tan IIA, APAP, NAPQI, Nrf2, ARE, MRP2/Mrp2, MRP4/Mrp4, HOTAIR, H3K4me3, H3K27me3
Keywords : Tanshinone IIA, Acetaminophen, Hepatotoxicity, Pharmacokinetic, HOTAIR-Nrf2-MRP2/4
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