Prediction of in vivo developmental toxicity by combination of Hand1-Luc embryonic stem cell test and metabolic stability test with clarification of metabolically inapplicable candidates. (30th September 2016)

• Record Type: Journal Article
• Authors: Nagahori, Hirohisa; Suzuki, Noriyuki; Le Coz, Florian; Omori, Takashi; Saito, Koichi
• Is Part Of: Toxicology letters. Volume 259(2016)
• Page Start: 44
• Page End: 51
• Publication Date: 2016-09-30
• Subjects: EST embryonic stem cell test -- ECVAM European Center for the Validation of Alternative Methods -- PBPK physiologically based pharmacokinetics -- MIC metabolically inapplicable candidate -- PBS phosphate buffered saline -- DMSO dimethyl sulfoxide -- MD maximum dose -- ESI electrospray ionization -- Rt retention time -- Fh hepatic availability -- ROC receiver operating characteristic curve -- PM prediction model -- IC50 the concentration that reduces the viability of cells to 50% -- ID50 the concentration that causes 50% inhibition in embryonic stem cell cardiac differentiation by 50% -- SE standard error -- CI confidence interval -- SD standard deviation -- CV coefficient of variance; Cytotoxicity -- In-vitro toxicity -- Metabolism -- Reproductive toxicity; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2016.07.022
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: A step-wise prediction with Hand1-Luc EST and metabolic stability test is proposed. Hand1-Luc EST of a total of 71 chemicals shows highly reproducible results. MICs potentially have a metabolic activation and accumulation properties. Exclusion of MICs significantly improves classification of developmental toxicity. Abstract: Hand1-Luc Embryonic Stem Cell Test (Hand1-Luc EST) is a promising alternative method for evaluation of developmental toxicity. However, the problems of predictivity have remained due to appropriateness of the solubility, metabolic system, and prediction model. Therefore, we assessed the usefulness of rat liver S9 metabolic stability test using LC–MS/MS to develop new prediction model. A total of 71 chemicals were analyzed by measuring cytotoxicity and differentiation toxicity, and highly reproducible (CV = 20%) results were obtained. The first prediction model was developed by discriminant analysis performed on a full dataset using Hand1-Luc EST, and 66.2% of the chemicals were correctly classified by the cross-validated classification. A second model was developed with additional descriptors obtained from the metabolic stability test to calculate hepatic availability, and an accuracy of 83.3% was obtained with applicability domain of 50.7% (=36/71) after exclusion of 22 metabolically inapplicable candidates, which potentially have a metabolic activation property. A step-wise prediction scheme with combination of Hand1-Luc EST and metabolic stability test was therefore proposed. The current results provide a promising in vitro test method for accurately predicting in vivo developmental toxicity.