High-content analysis/screening for predictive toxicology: application to hepatotoxicity and genotoxicity.
High-content imaging/analysis has emerged as a powerful tool for predictive toxicology as it can be used for identifying and mitigating potential safety risks during drug discovery. By careful selection of end-points, some cellular assays can show better predictivity than routine animal toxicity testing for certain adverse events. Here, we present the perhaps most utilized high-content screening assays for predictive toxicology in the pharmaceutical industry. Multi-parametric imaging of cell health in simple and cost-effective model systems can be used to predict human hepatotoxicity and elucidate mechanisms of toxicity, and imaging of bile salt transport inhibition in sandwich-cultured hepatocytes can be used to predict cholestasis-inducing compounds. Imaging of micronuclei formation in simple cell models can be used to detect genotoxic potential and elucidate anuegenic or clastogenic mode of actions. The hope is that application of these relatively predictive assays during drug discovery will reduce toxicity and safety-related attrition of drug development programmes at later stages.
Department of Exploratory Toxicology, Non-Clinical Safety Research, H. Lundbeck A/S, Valby, Denmark.
Mikael
M
Persson
Anni F
AF
Løye
Mélanie
M
Jacquet
Natacha S
NS
Mow
Annemette V
AV
Thougaard
Tomas
T
Mow
Jorrit J
JJ
Hornberg
D000818:Animals; D001647:Bile Acids and Salts / Q000037:antagonists & inhibitors / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis*; D002779:Cholestasis / Q000175:diagnosis; D003362:Cost-Benefit Analysis; D004249:DNA Damage / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods*
D001647:Bile Acids and Salts