Study Of Cardiac Toxicity And Acute Toxicity Using Zebrafish Model For Compounds

Objective①Exploring the relationship between zebrafish bradycardia model and hERGmodel as well as dog QT prolongation model in predicting the cardiac toxicity;②Exploringthe relationship between the zebrafish LC₅₀and the rodent oral LD₅₀.Methods①Incubated30QT interval prolongation drugs and8negative drugs with the48hpf zebrafish larvae which expressed the green fluorescent protein in heart, and recordedthe heart rate at4and16hours after administration of the drug so as to analyze therelationship between the zebrafish bradycardia and hERG model as well as the dog or humanQT prolongation in order to predict the potential cardiac toxicity for new drug candidates.②Incubated13compounds which had the data about acute toxicity in rodent in a seriesconcentrations with the4hpf,24hpf,48hpf and96hpf AB wild-type zebrafish for96h, andrecorded the results of the malformation and lethal to determine the LC₅₀. Conducted thelinear regression between the log LC₅₀of zebrafish verse log LD₅₀of rodents.Results①25out of30QT interval prolongation drugs in clinic caused bradycardia inzebrafish, while14out of16drugs induced QT prolongation in dog caused bradycardia inzebrafish; It was found that the QT prolongating drugs of5over30in human and2over16indog which did not show positive effect on zebrafish were antibiotic drugs. Except forantibiotic the bradycardia in zebrafish is well concordant with the human and dog QTprolongation results.21out of26drugs which blocked K+current in hERG experimentscaused bradycardia in zebrafish, and the relationship showed the coefficient correlationbetween zebrafish bradycardia and hERG was0.71. The8negative drugs had no effect onzebrafish heart rates.②The R²of the linear regression between rodent LD₅₀and zebrafishLC₅₀in4hpf,24hpf,48hpf and72hpf was0.86,0.89,0.89, and0.88respectively. The R²oflinear regression between corrected single concentration and rodent LD₅₀was0.90.Conclusions①The zebrafish bradycardia screening system could be used to predict thecardiac toxicity for the drug candidates.②Rodent oral LD₅₀could be predicted by using thezebrafish LC₅₀screening.