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A Combined in Vitro Approach to Improve the Prediction of Mitochondrial Toxicants – Free Reprint of Publication

A recent peer-reviewed publication in Toxicology in Vitro presents research by Cyprotex on methods to investigate drug- or chemical-induced mitochondrial toxicity.

Mitochondrial toxicity is a potentially very serious side effect that can play a role in drug- or chemical-induced organ failure. Mitochondria are essential organelles that a responsible for creation of ATP and providing energy for vital cellular functions, so mitochondrial stress or damage can have a debilitating impact. There has also been growing interest in in vitro mitochondrial toxicity assessment during drug discovery and development because its implication in both attrition and market withdrawal is on the rise.

The Glu/Gal assay is the current standard for evaluating mitochondrial risk by comparing the cytotoxicity of compounds in galactose media to glucose media. Because cells are more reliant on mitochondrial oxidative phosphorylation in galactose, they are also more sensitive to mitochondrial toxicants.

However, a more recent approach, made possible using the Seahorse XFe96 Flux Analyser provides mitochondrial toxicity data in real time by measuring oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and reserve capacity.

The publication explores if one approach is more predictive than the other, or if combining the two methods yields better results. The research concludes that the Seahorse assay was highly predictive and correctly identified 78% of the test compounds, all of which were known mitochondrial toxicants, compared to 41% identified by the Glu/Gal assay. However, the Glu/Gal assay did identify one compound that the Seahorse assay did not. By combining the assays, sensitivity was increased to 81%, specificity was 100% and accuracy was 92%. The Seahorse assay was also able to correctly identify the mechanism in over 76% of cases.

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