PUBLICATION
Mechanism of hepatotoxicity of first-line tyrosine kinase inhibitors: gefitinib and afatinib
- Authors
- Zhang, Y., Cai, Y., Zhang, S.R., Li, C.Y., Jiang, L.L., Wei, P., He, M.F.
- ID
- ZDB-PUB-210212-10
- Date
- 2021
- Source
- Toxicology letters 343: 1-10 (Journal)
- Registered Authors
- Keywords
- Afatinib, Apoptosis, Endoplasmic reticulum stress, Gefitinib, Hepatotoxicity, Zebrafish
- MeSH Terms
-
- Afatinib/toxicity*
- Animals
- Animals, Genetically Modified
- Chemical and Drug Induced Liver Injury/pathology*
- Embryo, Nonmammalian/drug effects*
- Gefitinib/toxicity*
- Gene Expression Regulation/drug effects
- Liver/drug effects*
- Liver/pathology
- Protein Kinase Inhibitors/toxicity*
- Zebrafish/embryology
- PubMed
- 33571620 Full text @ Toxicol. Lett.
- CTD
- 33571620
Citation
Zhang, Y., Cai, Y., Zhang, S.R., Li, C.Y., Jiang, L.L., Wei, P., He, M.F. (2021) Mechanism of hepatotoxicity of first-line tyrosine kinase inhibitors: gefitinib and afatinib. Toxicology letters. 343:1-10.
Abstract
Aims Both gefitinib and afatinib are epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in the treatment of non-small cell lung cancer (NSCLC). It has been reported that gefitinib and afatinib could cause hepatotoxicity during the clinic treatment, therefore it is critical to investigate their hepatotoxicity systematically. In this study, zebrafish (Danio rerio) were used as model animals to compare the hepatotoxicity and their toxic mechanism.
Main methods The zebrafish transgenic line [Tg (fabp10a: dsRed; ela3l:EGFP) was used in this study. After larvae developed at 3 days post fertilization (dpf), they were put into different concentrations of gefitinib and afatinib. At 6 dpf, the viability, liver area, fluorescence intensity, histopathology, apoptosis, transaminase reflecting liver function, the absorption of yolk sac, and the expression of relative genes were observed and analyzed respectively.
Key findings Both gefitinib and afatinib could induce the larvae hepatotoxicity dose-dependently. Based on the liver morphology, histopathology, apoptosis and function assessments, gefitinib showed higher toxicity, causing more serious liver damage. Both gefitinib and afatinib caused abnormal expressions of genes related to endoplasmic reticulum stress (ERS) pathway and apoptosis. For example, jnk, perk, bip, chop, ire1, bid, caspase3 and caspase9 were up-regulated, while xbp1s, grp78, bcl-2/bax, and caspase8 were down-regulated. The hepatotoxicity difference of gefitinib and afatinib might be due to the different expression level of related genes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping