Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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The Combination of Gefitinib and Acetaminophen Exacerbates Hepatotoxicity via ROS-Mediated Apoptosis

  • Jiangxin Xu (Department of Pharmacy, Hangzhou Red Cross Hospital (Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine)) ;
  • Xiangliang Huang (Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University) ;
  • Yourong Zhou (Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University) ;
  • Zhifei Xu (Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University) ;
  • Xinjun Cai (Department of Pharmacy, Hangzhou Red Cross Hospital (Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine)) ;
  • Bo Yang (Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University) ;
  • Qiaojun He (Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University) ;
  • Peihua Luo (Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University) ;
  • Hao Yan (Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University) ;
  • Jie Jin (Department of Pharmacy, Hangzhou Red Cross Hospital (Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine))
  • Received : 2023.11.28
  • Accepted : 2024.02.23
  • Published : 2024.09.01
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Abstract

Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it needs analgesics during oncology treatment, particularly in the context of the 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

Acknowledgement

This work was supported by National Natural Science Foundation of China (No.82104315), Natural Science Foundation of Zhejiang Province of China (No. LQ22H310002), Special Pharmacy Project of Zhejiang Pharmaceutical Association (No.2023ZYY31), Yangtze River Delta Health Scientific Research Project of Zhejiang Province (No.2023CSJ-3-A002) and Youth Fund Project of Hangzhou Red Cross Hospital (No. HHQN2023007).

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