Hepatotoxicity mediated by pyrazole (cytochrome P450 2E1) plus tumor necrosis factor alpha treatment occurs in c-Jun N-terminal kinase 2-/- but not in c-Jun N-terminal kinase 1−/− mice
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UNLABELLED: Cytochrome P450 2E1 (CYP2E1) induction and tumor necrosis factor alpha (TNF-α) production are key risk factors in alcoholic liver injury. Increased oxidative stress from CYP2E1 induction by pyrazole in vivo sensitizes the liver to TNF-α-induced hepatotoxicity by a mechanism involving the activation of c-jun N-terminal kinase (JNK) and mitochondrial damage. The aim of this study was to evaluate whether JNK1 or JNK2 plays a role in this potentiated hepatotoxicity. Wild-type (WT), jnk1(-/-) , and jnk2(-/-) mice were used to identify changes of hepatotoxicity, damage to mitochondria, and production of oxidative stress after pyrazole plus TNF-α treatment. Increased serum alanine aminotransferase, inflammatory infiltration, and central necrosis were observed in the jnk2(-/-) and WT mice treated with pyrazole plus TNF-α, but not in the jnk1(-/-) mice. Pyrazole elevated the activity and protein level of CYP2E1 in all mice. There was a significant increase of malondialdehyde, 4-hydroxynonenal adducts, 3-nitrotyrosine, and inducible nitric oxide synthase in the jnk2(-/-) and WT mice, compared to the jnk1(-/-) mice, upon pyrazole plus TNF-α treatment, or compared to mice treated with either pyrazole alone or TNF-α alone. The antioxidants, catalase, phospholipid hydroperoxide glutathione peroxidase, thioredoxin, and glutathione were lowered, and cytochrome c was released from the mitochondria in the jnk2(-/-) and WT mice. Mitochondrial production of superoxide was increased in the jnk2(-/-) and WT mice, compared to the jnk1(-/-) mice, upon pyrazole plus TNF-α treatment. Electron microscopy showed altered mitochondrial structure in the jnk2(-/-) and WT mice, but not the jnk1(-/-) mice. CONCLUSIONS: JNK1 plays a role in the hepatotoxicity, mitochondrial dysfunction, and oxidative stress mediated by pyrazole plus TNF-α treatment. These findings raise the question as to the potential mechanisms of JNK1 activation related to alcoholic liver injury.
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JNK1 seems critical in hepatotoxicity caused by co-treatment of pyrazole and TNFα.
“For instance, both JNK1 and JNK2 seem to be important in alcohol-induced fatty liver injury [111], while JNK1 seems critical in hepatotoxicity caused by co-treatment of pyrazole and TNFα [127].”
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Self-citation
- Authors
- Wang, X., Wu, D., Yang, L., & Cederbaum, A. I.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Cederbaum, Arthur I.
- Venue
- Hepatology
- Published
- 2011-11
- Volume
- 54
- Issue
- 5
- Pages
- 1753-1766
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3203340
- OpenAlex
- W2085143152
- Cited by
- 19
- References
- 33
- Citations by year
- 2023: 1 · 2021: 1 · 2019: 1 · 2018: 2 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 2
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01aa017425-03)
- National Institute on Alcohol Abuse and Alcoholism (R01AA003312, R01AA018790, R01 AA-017425)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- hepatotoxicity, pyrazole derivatives, CYP2E1 induction, TNF-α, JNK1, alcoholic liver injury, oxidative stress, mitochondrial dysfunction, cytochrome c release, superoxide production, lipid peroxidation, nitrosative stress, antioxidant enzymes
- MeSH terms
- Alanine Transaminase, Animals, Catalase, Enzyme Inhibitors, Female, Liver Diseases, Alcoholic, Male, Mice, Inbred C57BL, Mitochondria, Pyrazoles, Risk Factors, Tumor Necrosis Factor-alpha, Lipid Peroxidation, Mice, Knockout, Oxidative Stress, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Mice, Nitric Oxide Synthase Type II, Caspase 3, Caspase 8, Chemical and Drug Induced Liver Injury
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