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

Toxicol Sci. 2018 Mar 1;162(1):99-112. doi: 10.1093/toxsci/kfx230.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / toxicity
  • Animals
  • Antioxidants / metabolism
  • Antioxidants / therapeutic use*
  • Cell Line
  • Cell Survival / drug effects
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Chlorogenic Acid / metabolism
  • Chlorogenic Acid / therapeutic use*
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Liver Function Tests
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Polyphenols / metabolism
  • Polyphenols / therapeutic use*
  • Reactive Oxygen Species / metabolism


  • Antioxidants
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Polyphenols
  • Reactive Oxygen Species
  • Chlorogenic Acid
  • Acetaminophen