Natural Polyphenol Chlorogenic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Activating ERK/Nrf2 Antioxidative Pathway

Abstract

Hepatotoxicity due to acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure in clinic. Chlorogenic acid (CGA), a dietary polyphenol, was reported to prevent APAP-induced liver injury in our previous studies. This study aims to investigate the protection provided by CGA against APAP-induced hepatotoxicity via focusing on nuclear factor erythroid 2-related factor 2 (Nrf2) and extracellular regulated protein kinases (ERK)1/2. CGA prevented APAP-induced oxidative liver injury and enhanced Nrf2 activation in mice and in hepatocytes in vitro. CGA-provided the protection against APAP-induced hepatotoxicity was diminished after the application of Nrf2 siRNA in vitro and Nrf2 knockout mice in vivo. CGA enhanced the expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1), and their inhibitors reduced the protection provided by CGA against APAP-induced cytotoxicity in hepatocytes. Molecular docking results indicated the potential interaction of CGA with Nrf2 binding site in Kelch-like ECH-associating protein-1 (Keap1). CGA decreased the expression of protein phosphatases including PP2A subunit A (PP2A-A) and PP5, and induced the sustained ERK1/2 phosphorylation. Moreover, ERK1/2 inhibitors (U0126 and PD98059) and ERK2 siRNA abrogated CGA-induced Nrf2 phosphorylation and its subsequent transcriptional activation, and also reduced the protection provided by CGA against APAP-induced cytotoxicity in hepatocytes. These results suggest that CGA protects against APAP-induced hepatotoxicity by activating Nrf2 antioxidative signaling pathway via blocking the binding of Nrf2 to its inhibitor protein Keap1, and ERK1/2 plays a critical role in regulating CGA-induced Nrf2 transcriptional activation. CGA is a promising therapeutic agent for the detoxification of APAP-induced hepatotoxicity.

Detoxication mechanisms of Radix Tripterygium wilfordii via compatibility with Herba Lysimachia christinae in S180-bearing mice by involving Nrf2

“…Serum ALT and AST levels are sensitive parameters of liver function [ 35 ]. In the current study, compared with the normal group, S180 tumor-bearing induced the significant elevation of serum ALT and AST levels (both P <0.01) ( Figure 1 A,B).…”

“…Serum ALT and AST are sensitive indicators of liver function and their obvious elevation commonly indicates liver toxicity [ 35 ]. In the present study, compared with the normal group, serum ALT and AST levels were significantly elevated in the control group of mice, indicating tumor-bearing induced liver damage, which was consistent with the results reported in many literatures [ 45 , 47–50 ].…”

Bamboo Stems (Phyllostachys nigra variety henosis) Containing Polyphenol Mixtures Activate Nrf2 and Attenuate Phenylhydrazine-Induced Oxidative Stress and Liver Injury

“…Recently, chlorogenic acid was reported to be a promising therapeutic agent for the detoxification of acetaminophen-induced hepatotoxicity. Wei et al reported that chlorogenic acid protects against APAP-induced hepatotoxicity by activating Nrf2 signaling pathway by blocking the binding of Nrf2 to its inhibitor protein, Keap1; furthermore, ERK1/2 has been reported to play a critical role in regulating chlorogenic acid-induced Nrf2 transcriptional activation [42]. There have been many report one the pleiotropic effect of polyphenol mixture and nutrients combination against various cancers including liver cancer [43].…”

Herbal Therapy for the Treatment of Acetaminophen-Associated Liver Injury: Recent Advances and Future Perspectives

“…However, green tea extract potentiated APAPinduced hepatotoxicity when applied after APAP treatment through causing glutathione depletion, indicating importance of the supplement interactions. Recently, Wei et al (2018) found that the natural polyphenol chlorogenic acid is protective against APAP-induced hepatotoxicity through activation of Nrf2 antioxidant signalling pathway by blocking the binding of Nrf2 to Keap1. In addition, ERK1/2 plays a critical role in regulation of the polyphenol chlorogenic acid-derived Nrf2 transcriptional activation.…”