Modern approaches to chemical toxicity screening

Abstract

Chemical toxicity has a serious impact on public health, and toxicity failures of drug candidates drive up drug development costs. Many in vitro bioassays exist for toxicity screening, and newer versions of these tend to be high throughput or high content assays, some of which rely on electrochemical detection. Toxicity very often results from metabolites of the chemicals we are exposed to, so it is important that assays feature metabolic conversion. Combining bioassays, computational predictions, and accurate chemical pathway elucidation presents our best chance for reliable toxicity prediction. Employing electrochemical and electrochemiluminescent approaches, cell-free microfluidic arrays can measure relative rates of formation of DNA-metabolite adduct formation (a measure of genotoxicity) as well as DNA oxidation levels resulting from enzyme-generated metabolites. Enzymes for several organ types can be studied simultaneously. These arrays can be used to identify the most reactive metabolites, and subsequent mechanistic details can then be investigated with high throughput LC-HPLC using enzyme/DNA-coated magnetic beads.

Human iPSC-Based Modeling of Central Nerve System Disorders for Drug Discovery

“…Such discrepancies result largely from different enzyme-generated metabolites. Specifically, bioactivation is a metabolic process where reactive species are generated and lead to genotoxicity, covalent adducts, reactive oxidation species, and idiosyncratic drug reactions [ 185 ]. Animal models are not reliable in predicting reactive metabolites because their metabolic processes are naturally estranged from the human physiology.…”

“…High content analysis (HCA) and high-throughput screening (HTS) have become a preferred strategy for toxicity screening in drug development. Many of these approaches incorporate fluorescent probes in cellular sites to monitor multiple toxicity endpoints and phenotypic changes measured by multi-color visualization [ 185 ]. Novel modifications have further extended HTS applications, which include biologically compatible nanomaterials like zinc oxide nanowires to monitor microsome metabolism as well as electrochemical impedance spectroscopy to assess the drug toxicity by detecting morphological alterations of HeLa cells or fibroblasts in a 3D-hydrogel flow array.…”