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Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice.

Abstract Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury.
PMID
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Authors

Mayor MeshTerms
Keywords

Acetaminophen

Acute liver injury

p62-keap1-Nrf2 antioxidant pathway

Journal Title chemico-biological interactions
Publication Year Start




PMID- 29331651
OWN - NLM
STAT- Publisher
LR  - 20180114
IS  - 1872-7786 (Electronic)
IS  - 0009-2797 (Linking)
DP  - 2018 Jan 10
TI  - Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of
      acetaminophen-induced acute liver injury in mice.
LID - S0009-2797(17)30792-5 [pii]
LID - 10.1016/j.cbi.2018.01.008 [doi]
AB  - Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly
      half of drug-induced liver injury is attributed to APAP in the US and many
      European countries. Oxidative stress has been validated as a critical event
      involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor
      protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to
      oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway
      in APAP-induced hepatotoxicity remains unknown. In the present study, the
      dose-response and time-course model in C57/BL6 mice were established by
      intraperitoneal injection of APAP. The results of serum alanine/aspartate
      aminotransferases (ALT/AST) and histological examination demonstrated that APAP
      overdose resulted in the severe liver injury. In the meantime, the levels of p62,
      phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, 
      suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression
      of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of 
      HO-1 and GCLC were decreased with the increase of APAP dose. Our further
      investigation found that expression of HO-1 and GCLC peaked at 3h approximately
      6h, and then were decreased gradually. Taken together, these results indicated
      that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early
      stage of APAP hepatotoxicity, which might play a protective role in the process
      of APAP-induced acute liver injury.
CI  - Copyright (c) 2018. Published by Elsevier B.V.
FAU - Shen, Zhenyu
AU  - Shen Z
AD  - Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan,
      Shandong, 250012, PR China.
FAU - Wang, Yu
AU  - Wang Y
AD  - Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan,
      Shandong, 250012, PR China.
FAU - Su, Zhenhui
AU  - Su Z
AD  - Department of Pathology, Shandong Provincial Hospital, 324 Jingwu-Weiqi Road,
      Jinan, Shandong, 250021, PR China.
FAU - Kou, Ruirui
AU  - Kou R
AD  - Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan,
      Shandong, 250012, PR China.
FAU - Xie, Keqin
AU  - Xie K
AD  - Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan,
      Shandong, 250012, PR China.
FAU - Song, Fuyong
AU  - Song F
AD  - Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan,
      Shandong, 250012, PR China. Electronic address: [email protected]
LA  - eng
PT  - Journal Article
DEP - 20180110
PL  - Ireland
TA  - Chem Biol Interact
JT  - Chemico-biological interactions
JID - 0227276
OTO - NOTNLM
OT  - Acetaminophen
OT  - Acute liver injury
OT  - p62-keap1-Nrf2 antioxidant pathway
EDAT- 2018/01/15 06:00
MHDA- 2018/01/15 06:00
CRDT- 2018/01/15 06:00
PHST- 2017/07/28 00:00 [received]
PHST- 2017/12/02 00:00 [revised]
PHST- 2018/01/09 00:00 [accepted]
PHST- 2018/01/15 06:00 [entrez]
PHST- 2018/01/15 06:00 [pubmed]
PHST- 2018/01/15 06:00 [medline]
AID - S0009-2797(17)30792-5 [pii]
AID - 10.1016/j.cbi.2018.01.008 [doi]
PST - aheadofprint
SO  - Chem Biol Interact. 2018 Jan 10. pii: S0009-2797(17)30792-5. doi:
      10.1016/j.cbi.2018.01.008.