Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2023.209
The Combination of Gefitinib and Acetaminophen Exacerbates Hepatotoxicity via ROS-Mediated Apoptosis
Jiangxin Xu1,†, Xiangliang Huang2,†, Yourong Zhou2, Zhifei Xu2, Xinjun Cai1, Bo Yang3,4, Qiaojun He2,5, Peihua Luo2,6, Hao Yan2,* and Jie Jin1,*
1Department of Pharmacy, Hangzhou Red Cross Hospital (Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine), Hangzhou 310005,
2Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058,
3Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058,
4School of Medicine, Hangzhou City University, Hangzhou 310015,
5Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018,
6Department of Pharmacology and Toxicology, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310018, China
*E-mail: yh925@zju.edu.cn (Yan H), jinjie0916@163.com (Jin J)
Tel: +86-0571-88206915 (Yan H), +86-0571-56109730 (Jin J)
Fax: +86-0571-88208400 (Yan H), +86-0571-56109598 (Jin J)
The first two authors contributed equally to this work.
Received: November 28, 2023; Revised: February 18, 2024; Accepted: February 23, 2024; Published online: June 14, 2024.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it need for analgesics during oncology treatment, particularly in the context ofthe coronavirus disease, where patients are more susceptible to contract high fever and sore throat. This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression. Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.
Keywords: Gefitinib, Acetaminophen, Hepatotoxicity, Autophagy, ROS


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