PUBLICATION
Liver toxicity of macrolide antibiotics in zebrafish
- Authors
- Zhang, M.Q., Chen, B., Zhang, J.P., Chen, N., Liu, C.Z., Hu, C.Q.
- ID
- ZDB-PUB-200527-9
- Date
- 2020
- Source
- Toxicology 441: 152501 (Journal)
- Registered Authors
- Keywords
- ADMET, Differentially expressed genes, Liver toxicity, RNA-seq analysis, c-Fos, macrolides
- MeSH Terms
-
- Animals
- Anti-Bacterial Agents/toxicity*
- Blotting, Western
- Chemical and Drug Induced Liver Injury/diagnostic imaging
- Chemical and Drug Induced Liver Injury/etiology*
- Chemical and Drug Induced Liver Injury/pathology
- Computer Simulation
- Fatty Liver/chemically induced
- Gene Expression/drug effects
- Larva
- Liver/diagnostic imaging
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Luminescent Proteins/metabolism
- Macrolides/toxicity*
- Optical Imaging
- Real-Time Polymerase Chain Reaction
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 32454074 Full text @ Toxicology
- CTD
- 32454074
Citation
Zhang, M.Q., Chen, B., Zhang, J.P., Chen, N., Liu, C.Z., Hu, C.Q. (2020) Liver toxicity of macrolide antibiotics in zebrafish. Toxicology. 441:152501.
Abstract
Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections, but macrolides also expose people to the risk of adverse events include hepatotoxicity. Here, we report the liver toxicity of macrolides with different structures in zebrafish. The absorption, distribution, metabolism, excretion and toxicology (ADMET) parameters of macrolide compounds were predicted and contrasted by utilizing in silico analysis. Fluorescence imaging and Oil Red O stain assays showed all the tested macrolide drugs induced liver degeneration, changed liver size and liver steatosis in larval zebrafish. Through RNA-seq analysis, we found seven co-regulated differentially expressed genes (co-DEGs) associated with metabolism, apoptosis and immune system biological processes, and two co-regulated significant pathways including amino sugar and nucleotide sugar metabolism and apoptosis signaling pathway. We found that only fosab of seven co-DEGs was in the two co-regulated significant pathways. fosab encoded proto-oncogene c-Fos, which was closely associated with liver diseases. The whole-mount in situ hybridization showed high transcription of c-Fos induced by macrolide compounds mainly in the liver region of zebrafish larvae. Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) leakage assays revealed that macrolides exerts significant cytotoxic effects on L02 cells. qRT-PCR and western blot analysis demonstrated macrolides also promoted human c-Fos expression in L02 cells. The c-Fos overexpression significantly reduced cell viability by using CCK-8 assay. These data indicate that hepatotoxicity induced by macrolides may be correlated with c-Fos expression activated by these compounds. This study may provide a biomarker for the further investigations on the mechanism of hepatotoxicity induced by macrolide drugs with different structures, and extend our understanding for improving rational clinical application of macrolides.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping