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Published on: May 29, 2020
Montelukast Prevents Mice Against Acetaminophen-Induced Liver Injury
Shiyun Pu1, Qinhui Liu2, Yanping Li2
1Department of Pharmacy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
Abstract:
Acetaminophen (APAP) is a widely used over-the-counter antipyretic and analgesic drug. Overdose of APAP is the leading cause of hospital admission for acute liver failure. Montelukast is an antagonist of cysteinyl leukotriene receptor 1 (Cysltr1), which protects from inflammation and oxidative stress. However, the function of montelukast in APAP-induced hepatotoxicity remains unknown. In this study, we examined whether pharmacological inhibition of Cystlr1 could protect mice against APAP-induced hepatic damage. We found that APAP treatment upregulated messenger RNA and protein levels of Cysltr1 both in vitro and in vivo. Pharmacological inhibition of Cysltr1 by montelukast ameliorated APAP-induced acute liver failure. The hepatoprotective effect of montelukast was associated with upregulation of hepatic glutathione/glutathione disulfide level, reduction in c-Jun-NH2-terminal kinase activation and oxidative stress. In mouse primary hepatocytes, inhibition of Cysltr1 by montelukast ameliorated the expression of inflammatory-related genes and APAP-induced cytotoxicity. We conclude that montelukast may be used to treat APAP-induced acute hepatic injury.
Insights
Montelukast protects against acetaminophen-induced liver injury by inhibiting Cysltr1. This drug may offer a new treatment for acute liver damage caused by acetaminophen overdose.
Area of Science:
- Pharmacology
- Hepatology
- Toxicology
Background:
- Acetaminophen (APAP) overdose is a primary cause of acute liver failure.
- Montelukast, a Cysltr1 antagonist, is known for anti-inflammatory and antioxidant properties.
- The role of montelukast in APAP-induced hepatotoxicity was previously uninvestigated.
Purpose of the Study:
- To investigate the protective effects of montelukast against APAP-induced liver damage in mice.
- To determine if pharmacological inhibition of Cysltr1 could mitigate APAP hepatotoxicity.
Main Methods:
- Mice were treated with APAP to induce hepatotoxicity.
- Cysltr1 expression (mRNA and protein) was analyzed in vitro and in vivo.
- The effects of montelukast on APAP-induced liver injury, oxidative stress, and inflammation were assessed.
- Primary mouse hepatocytes were used to evaluate montelukast's impact on cytotoxicity and inflammatory gene expression.
Main Results:
- APAP treatment upregulated Cysltr1 expression.
- Montelukast administration ameliorated APAP-induced acute liver failure.
- Hepatoprotective effects were linked to increased glutathione levels, reduced JNK activation, and decreased oxidative stress.
- Montelukast inhibited inflammatory gene expression and reduced APAP-induced cytotoxicity in primary hepatocytes.
Conclusions:
- Pharmacological inhibition of Cysltr1 by montelukast demonstrates significant hepatoprotective effects against APAP-induced liver injury.
- Montelukast may serve as a potential therapeutic agent for treating acute liver damage resulting from acetaminophen overdose.
