title: Validation of visualized transgenic zebrafish as a high throughput model to assay bradycardia related cardio toxicity risk candidates.
abstract: Drug-induced QT prolongation usually leads to torsade de pointes (TdP), thus for drugs in the early phase of development this risk should be evaluated. In the present study, we demonstrated a visualized transgenic zebrafish as an in vivo high-throughput model to assay the risk of drug-induced QT prolongation. Zebrafish larvae 48 h post-fertilization expressing green fluorescent protein in myocardium were incubated with compounds reported to induce QT prolongation or block the human ether-a-go-go-related gene (hERG) K⁺ current. The compounds sotalol, indapaminde, erythromycin, ofoxacin, levofloxacin, sparfloxacin and roxithromycin were additionally administrated by microinjection into the larvae yolk sac. The ventricle heart rate was recorded using the automatic monitoring system after incubation or microinjection. As a result, 14 out of 16 compounds inducing dog QT prolongation caused bradycardia in zebrafish. A similar result was observed with 21 out of 26 compounds which block hERG current. Among the 30 compounds which induced human QT prolongation, 25 caused bradycardia in this model. Thus, the risk of compounds causing bradycardia in this transgenic zebrafish correlated with that causing QT prolongation and hERG K⁺ current blockage in established models. The tendency that high logP values lead to high risk of QT prolongation in this model was indicated, and non-sensitivity of this model to antibacterial agents was revealed. These data suggest application of this transgenic zebrafish as a high-throughput model to screen QT prolongation-related cardio toxicity of the drug candidates.
authors: South China University of Technology, Guangzhou 510641, China.
authors: Dingsheng
authors: D
authors: Wen
authors: Aiming
authors: A
authors: Liu
authors: Feng
authors: F
authors: Chen
authors: Julin
authors: J
authors: Yang
authors: Renke
authors: R
authors: Dai
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001919:Bradycardia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D015507:Drugs, Investigational / Q000009:adverse effects*; D004487:Edema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007814:Larva / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008845:Microinjections; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D010493:Pericarditis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D010496:Pericardium / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
chemical_list: D015507:Drugs, Investigational; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins