Emily Minner

Background: Acetaminophen is the most used over-the-counter analgesic in the United States.¹ Without careful review of the active ingredients in a drug, it can be easy to accidentally ingest a toxic amount of acetaminophen.¹ Acetaminophen overdose is the result of 56,000 emergency visits, 2,600 hospitalizations, and 500 deaths annually.¹ Approximately 50% of acetaminophen overdoses are accidental.² The current standard of care for acetaminophen overdose is administration of N-acetylcysteine (NAC). NAC acts through the same pathway as reduced glutathione and it also restores glutathione, which serves to lower the amount of N-acetyl-p-benzoquinone imine (NAPQI) in the body.³ NAC can prevent hepatic injury if administered within 8 hours, however, it has been shown to have reduced therapeutic effects if administered up to 24 hours post-ingestion.³ Once NAPQI has been generated, oxidative stress has begun and the JNK/MAPK, as well as other pathways of apoptosis, have been activated and liver injury has begun.⁴

Research Objectives: The purpose of this study is to identify potential future targets and methods for treatment of acetaminophen induced liver injury that would extend the therapeutic administration window past that of current treatment.

Methods: A PubMed search was conducted using the terms acetaminophen, JNK/MAPK pathway, and hepatic injury.

Results: The JNK/MAPK pathway has been shown to be active in hepatic injury in both low and high-dose acetaminophen exposure, unlike the depletion of glutathione.⁵ Studies of the differentially expressed genes in mice suffering from acetaminophen toxicity have found JUN (JNK) to be the most important gene in acute liver failure, validating its potential as a future target for protection against acetaminophen induced acute liver failure.⁶

Studies have found that administration of hydrogen sulfide following generation of oxidative stress reduces the phosphorylation of the JUN signaling protein. Blocking its phosphorylation inhibits JUN’s ability to activate the downstream signaling proteins, preventing it from increasing transcription of additional pro-apoptotic proteins and pro-inflammatory cytokines.⁷ Administration of hydrogen sulfide has shown success in preventing apoptosis through inhibition of the JNK/MAP signaling pathway in oxidative stress generated by reperfusion injury in the kidneys, cyclophosphamide administration in the liver, and acetaminophen induced acute liver injury.^6,7,8

Conclusion: These results have shown that H2S may have therapeutic effects if administered post generation of oxidative stress in acetaminophen induced acute liver failure. This new therapy could potentially improve treatment past NAC’s current therapeutic window, before toxic ingestion, or after chronic abuse.

Works Cited:

1. Agrawal S, Khazaeni B. Acetaminophen Toxicity. [Updated 2022 Aug 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441917/
2. Ramachandran A, Jaeschke H. Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives. Gene Expr. 2018;18(1):19-30. doi:10.3727/105221617X15084371374138
3. Saito C, Zwingmann C, Jaeschke H. Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology. 2010;51(1):246-254. doi:10.1002/hep.23267
4. Chiew, Angela L, and Nicholas A Buckley. “Acetaminophen Poisoning.” Critical care clinics vol. 37,3 (2021): 543-561. doi:10.1016/j.ccc.2021.03.005
5. Hu J, Ramshesh VK, McGill MR, Jaeschke H, Lemasters JJ. Low Dose Acetaminophen Induces Reversible Mitochondrial Dysfunction Associated with Transient c-Jun N-Terminal Kinase Activation in Mouse Liver. Toxicol Sci. 2016;150(1):204-215. doi:10.1093/toxsci/kfv319
6. Li, Xiaoyong et al. “Hydrogen sulfide protects against acetaminophen-induced acute liver injury by inhibiting apoptosis via the JNK/MAPK signaling pathway.” Journal of cellular biochemistry vol. 120,3 (2019): 4385-4397. doi:10.1002/jcb.27724
7. Abdel-Latif R, Heeba GH, Hassanin SO, Waz S, Amin A. TLRs-JNK/ NF-κB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity. Front Pharmacol. 2022;13:850066. Published 2022 Apr 20. doi:10.3389/fphar.2022.850066
8. Azizi F, Seifi B, Kadkhodaee M, Ahghari P. Administration of hydrogen sulfide protects ischemia reperfusion-induced acute kidney injury by reducing the oxidative stress. Ir J Med Sci. 2016;185(3):649-654. doi:10.1007/s11845-015-1328-z