PUBLICATION
Cardiac safety evaluation in zebrafish and in silico ADME prediction of cephalosporins with an aminothiazoyl ring at the C-7 position
- Authors
- Han, Y., Chen, B., Zhang, J., Hu, C.
- ID
- ZDB-PUB-180330-10
- Date
- 2018
- Source
- Toxicology and applied pharmacology 347: 33-44 (Journal)
- Registered Authors
- Zhang, Jing-pu
- Keywords
- Biomarkers, Cardiac toxicity, Embryo, Predictive toxicology, Zebrafish
- MeSH Terms
-
- Animals
- Anti-Bacterial Agents/chemistry
- Anti-Bacterial Agents/pharmacokinetics
- Anti-Bacterial Agents/toxicity*
- Cardiotoxicity
- Cephalosporins/chemistry
- Cephalosporins/pharmacokinetics
- Cephalosporins/toxicity*
- Dose-Response Relationship, Drug
- Embryo, Nonmammalian/drug effects*
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/pathology
- Gene Expression Regulation, Developmental/drug effects
- Gene Regulatory Networks/drug effects
- Heart/drug effects*
- Heart/embryology
- Heart/physiopathology
- Heart Defects, Congenital/chemically induced*
- Heart Defects, Congenital/genetics
- Heart Defects, Congenital/metabolism
- Heart Defects, Congenital/physiopathology
- Molecular Docking Simulation
- Molecular Structure
- Protein Interaction Maps
- Risk Assessment
- Structure-Activity Relationship
- Systems Biology/methods*
- Thiazoles/chemistry
- Thiazoles/pharmacokinetics
- Thiazoles/toxicity*
- Toxicology/methods*
- Transcription, Genetic/drug effects
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 29596928 Full text @ Tox. App. Pharmacol.
- CTD
- 29596928
Citation
Han, Y., Chen, B., Zhang, J., Hu, C. (2018) Cardiac safety evaluation in zebrafish and in silico ADME prediction of cephalosporins with an aminothiazoyl ring at the C-7 position. Toxicology and applied pharmacology. 347:33-44.
Abstract
Systems toxicology approaches have been used as important tools in the drug discovery and medicine quality control processes. The aim of this study was to assess the pharmacokinetic and toxicity properties of cephalosporins with an aminothiazoyl ring at the C-7 position (CATRs). Cardiac toxicity of the compounds was assessed in zebrafish embryos, and it was determined that CATRs disturbed the formation and development of the heart in a dose-dependent manner. Differentially expressed genes (DEGs) related to the heart were also identified by transcriptome analysis, and co-DEGs were obtained in the protein-protein interaction (PPI) network. Several Gene Ontology (GO) terms and pathways that were enriched by DEGs were identified, and the most significantly enriched pathways were adrenergic signaling in cardiomyocytes, cardiac muscle contraction, and vascular smooth muscle contraction. Combined molecular docking results elucidated that cardiac toxicity mainly depends on the mother nucleus structure 7-aminocephalosporanic acid (7-ACA). The predicted absorption, distribution, metabolism and excretion (ADME) profile suggests that there is a modification at the C-3 side chain of 7-ACA that could change the compound distribution in vivo. The 7-ACA mother nucleus is responsible for the CATRs induced cardiac toxicity, and the three DEGs (nppa, adra2c, and tnni1c) may potentially be utilized as novel biomarkers for CATRs. Our results show that zebrafish embryos may be used to reveal the pathways of cardiac toxicity and they play a vital role in drug safety assessments.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping