title: Predicted drug-induced bradycardia related cardio toxicity using a zebrafish in vivo model is highly correlated with results from in vitro tests.
abstract: Several in vivo and in vitro studies have assessed methods of evaluating the cardio toxicity of compounds during drug development due to its importance for predicting human toxicity. However, in vivo/in vitro relationships have not yet been reported using a zebrafish model. This study determined the bradycardia of 15 compounds by evaluating the change in heart beat rate (HBR) in zebrafish, hERG fluorescence polarization (hERG-FP), and ionic current change using a patch clamp (hERG-PC). In addition, a model for prediction of drug-induced bradycardia was established using in vivo and in vitro assays designed for high-throughput toxicological screening. The IC(50) values correlated well in two in vitro studies (R(2)=0.9). The change in HBR in zebrafish caused by the compounds could be estimated using the IC(50) from the hERG-FP assay [(i.e., % of HBR=19.5×log(IC(50), hERG-FP)] or hERG-PC assay [(i.e., % of HBR=19.6×log(IC(50), hERG-FP)]. To validate the predictive model, 10 unknown compounds were used and the percentages of the HBR were estimated using the model. The observed and predicted HBR% for the compounds in zebrafish were well-correlated (R(2)=0.948). Therefore, the proposed models were useful for prediction of drug-induced bradycardia related cardio toxicity.
authors.affiliation: Bioorganic Science Division, Korea Research Institute of Chemical Technology, Jang-Dong 100, Yuseong, Daejeon, 305-600, South Korea.
authors.forename: Myoung Joo
authors.initials: MJ
authors.lastname: Park
authors.forename: Kyeong-Ryoon
authors.initials: KR
authors.lastname: Lee
authors.forename: Dae-Seop
authors.initials: DS
authors.lastname: Shin
authors.forename: Hang-Suk
authors.initials: HS
authors.lastname: Chun
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
mesh_terms: D000818:Animals; D001688:Biological Products; D001919:Bradycardia / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005454:Fluorescence Polarization; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D018408:Patch-Clamp Techniques; D010600:Pharmacology / Q000379:methods*; D011237:Predictive Value of Tests; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D000071230:Transcriptional Regulator ERG; D015027:Zebrafish
chemical_list: D001688:Biological Products; C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C030804:soedomycin