Evaluation of in Vitro Mitochondrial Toxicity Assays and Physicochemical Properties for Prediction of Organ Toxicity Using 228 Pharmaceutical Drugs

Mitochondrial toxicity has been shown to contribute to a variety of organ toxicities such as liver, cardiac, and kidney. In the past decades, two high-throughput applicable screening assays (isolated rat liver mitochondria; glucose-galactose grown HepG2 cells) to assess mitochondrial toxicity have been deployed in many pharmaceutical companies, and numerous publications have demonstrated its usefulness for mechanistic investigations. However, only two publications have demonstrated the utility of these screens as a predictor of human drug-induced liver injury. In the present study, we screened 73 hepatotoxicants, 46 cardiotoxicants, 49 nephrotoxicants, and 60 compounds not known to cause human organ toxicity for their effects on mitochondrial function(s) in the assays mentioned above. Predictive performance was evaluated using specificity and sensitivity of the assays for predicting organ toxicity. Our results show that the predictive performance of the mitochondrial assays are superior for hepatotoxicity...