C-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity

Gunawan, Basuki K.; Liu, Zhang–Xu; Han, Derick; Hanawa, Naoko; Gaarde, William A.; Kaplowitz, Neil

doi:10.1053/j.gastro.2006.03.045

Cited by 471Drug-Induced Hepatotoxicity and ProtectionLiver physiology and pathologyCell death mechanisms and regulation

C-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity

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Gunawan, Basuki K., Liu, Zhang–Xu, Han, Derick, Hanawa, Naoko, Gaarde, William A., Kaplowitz, Neil·2006·Gastroenterology

DOI 10.1053/j.gastro.2006.03.045

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Abstract

Background & aims In searching for effects of acetaminophen (APAP) on hepatocytes downstream of its metabolism that may participate in hepatotoxicity, we examined the role of stress kinases.Methods Mouse hepatocytes and C57BL/6 mice were administered a toxic dose of APAP with or without SP600125, a chemical c-jun N-terminal kinase (JNK) inhibitor. JNK activity as reflected in phospho-c-jun levels, serum alanine transaminase (ALT), and liver histology were assessed. Similar experiments were repeated in JNK1 and JNK2 knockout mice and by using antisense oligonucleotide (ASO) to knockdown JNK.Results Sustained activation of JNK was observed in cultured mouse hepatocytes and in vivo in the liver after APAP treatment. The importance of this pathway was identified by the marked protective effect of SP600125 against APAP toxicity in vitro and in vivo. The specificity of this protective effect was confirmed in vivo by the knockdown of JNK1 and 2 using ASO pretreatment. JNK2 knockout mice and mice treated with JNK2 ASO exhibited partial protection against APAP. One potential target of JNK is Bax translocation, which was enhanced by APAP and blocked by the JNK inhibitor. Protection by the JNK inhibitor persisted in Kupffer cell-depleted mice, whereas there was no protection against CCl(4) or concanavalin A toxicity.Conclusions This work suggests that JNK acts downstream of APAP metabolism to promote hepatotoxicity. The results suggest that JNK2 plays a predominant role, although maximum protection was seen with decrease in both forms of JNK.

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JNK2 plays a dominant role in APAP-induced acute liver injury since JNK2-null mice are resistant to acute hepatotoxicity.
“In contrast, JNK2 plays a dominant role in APAP-induced acute liver injury since JNK2-null mice are resistant to acute hepatotoxicity [113], suggesting that this area needs further clarification.”
From Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications (2014) · cites this paper as [113]

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Uehara T, Bennett B, Sakata S, Satoh Y, Bilter G, Westwick J, Brenner DA. JNK mediates hepatis ischemia perfusion injury. J Hepatol 2005;42:850 -859. Received August 18, 2005. Accepted March 23, 2006.
Zonal Ave., HMR 101, Los Angeles, California 90033. e-mail: gbasuki@usc.edu; fax: (323) 442-3243. Supported by NIH grants DK30312 and DK48522; a postdoctoral training award from the Los Angeles Chapter of The American Liver Foundation (to B.K.G.); a postdoctoral training award from the Garrie- Budnick Foundation (to D.H.); and an NIH KO1 award (DK67149; to Z-X.L.).

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Authors: Gunawan, B. K., Liu, Z., Han, D., Hanawa, N., Gaarde, W. A., & Kaplowitz, N.
Affiliations: University of Southern California (US)
Corresponding author: Gunawan, Basuki K.
ORCID: Liu, Zhang–Xu
Han, Derick
Kaplowitz, Neil
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2006-07
Volume: 131
Issue: 1
Pages: 165-178
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2006.03.045
OpenAlex: W1997037955
Cited by: 471
References: 59
Citations by year: 2026: 6 · 2025: 14 · 2024: 24 · 2023: 24 · 2022: 13 · 2021: 21 · 2020: 33 · 2019: 24 · 2018: 23 · 2017: 27 · 2016: 20 · 2015: 29 · 2014: 37 · 2013: 30 · 2012: 37
FWCI: 22.18
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Gastroenterology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (1k01dk067149-01)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-30312, K01 DK67149, DK48522, P30DK048522)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords: c-Jun N-terminal kinase, acetaminophen hepatotoxicity, JNK2, JNK1, SP600125, Bax translocation, hepatocyte apoptosis, Kupffer cells, JNK inhibitor, antisense oligonucleotide knockdown, acetaminophen metabolism
MeSH terms: Acetaminophen, Alanine Transaminase, Animals, Anthracenes, Cells, Cultured, Disease Models, Animal, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mitochondria, Liver, Blotting, Western, Apoptosis, Analgesics, Non-Narcotic, Hepatocytes, JNK Mitogen-Activated Protein Kinases, Mice, Chemical and Drug Induced Liver Injury

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C-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity

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