PMID- 29136249
OWN - NLM
STAT- MEDLINE
DCOM- 20190207
LR  - 20190215
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 162
IP  - 1
DP  - 2018 Mar 1
TI  - Natural Polyphenol Chlorogenic Acid Protects Against Acetaminophen-Induced 
      Hepatotoxicity by Activating ERK/Nrf2 Antioxidative Pathway.
PG  - 99-112
LID - 10.1093/toxsci/kfx230 [doi]
AB  - 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.
FAU - Wei, Mengjuan
AU  - Wei M
AD  - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key 
      Laboratory of Complex Prescription and The SATCM Key Laboratory for New Resources 
      and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, 
      Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
FAU - Zheng, Zhiyong
AU  - Zheng Z
AD  - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key 
      Laboratory of Complex Prescription and The SATCM Key Laboratory for New Resources 
      and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, 
      Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
FAU - Shi, Liang
AU  - Shi L
AD  - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key 
      Laboratory of Complex Prescription and The SATCM Key Laboratory for New Resources 
      and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, 
      Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
FAU - Jin, Yao
AU  - Jin Y
AD  - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key 
      Laboratory of Complex Prescription and The SATCM Key Laboratory for New Resources 
      and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, 
      Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
FAU - Ji, Lili
AU  - Ji L
AD  - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key 
      Laboratory of Complex Prescription and The SATCM Key Laboratory for New Resources 
      and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, 
      Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Antioxidants)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Polyphenols)
RN  - 0 (Reactive Oxygen Species)
RN  - 318ADP12RI (Chlorogenic Acid)
RN  - 362O9ITL9D (Acetaminophen)
SB  - IM
MH  - Acetaminophen/toxicity
MH  - Animals
MH  - Antioxidants/metabolism/*therapeutic use
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Chemical and Drug Induced Liver Injury/etiology/metabolism/*prevention & control
MH  - Chlorogenic Acid/metabolism/*therapeutic use
MH  - Humans
MH  - Liver/drug effects/metabolism
MH  - Liver Function Tests
MH  - MAP Kinase Signaling System/*drug effects
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred ICR
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Polyphenols/metabolism/*therapeutic use
MH  - Reactive Oxygen Species/metabolism
EDAT- 2017/11/15 06:00
MHDA- 2019/02/08 06:00
CRDT- 2017/11/15 06:00
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2019/02/08 06:00 [medline]
PHST- 2017/11/15 06:00 [entrez]
AID - 4616612 [pii]
AID - 10.1093/toxsci/kfx230 [doi]
PST - ppublish
SO  - Toxicol Sci. 2018 Mar 1;162(1):99-112. doi: 10.1093/toxsci/kfx230.