A high-throughput dual parameter assay for assessing drug-induced mitochondrial dysfunction provides additional predictivity over two established mitochondrial toxicity assays

The Acute Extracellular Flux (XF) Assay to Assess Compound Effects on Mitochondrial Function

“…If a drug displays a mitochondrial liability, oxygen consumption would be affected and extracellular acidification may increase concomitantly as cells try to circumvent the mitochondrial insult through increased glycolytic flux. 9 Such measurements allow analysis of the alterations and interplay of these pathways in cells and also facilitate mechanistic studies of compound effects on these energy pathways.…”

Mitochondrial toxicity assessment in industry – a decade of technology development and insight

“…For drugs with multiple off-target effects, toxicity is likely to be equal in both cell lines [17]. As demonstrated by Hynes et al [20], the glucose--galactose assay only detects about 2 --5% of all mitotoxicants, which underscores the contention that most compounds that cause organ toxicity do so via multiple off-target mechanisms. The abovementioned RST assay is often used as a follow-up to assess potential mitochondrial toxicity, and a modified version of glucose--galactose [21] has been commercialized [22].…”

Inhibition of bile canalicular network formation in rat sandwich cultured hepatocytes by drugs associated with risk of severe liver injury

“…It is notable that amiodarone, flutamide, benzbromarone, and troglitazone are well-known hepatotoxic drugs, as previously demonstrated in other conventional hepatocyte toxicity assays (Hynes et al, 2013;Kaufmann et al, 2005;Tolosa et al, 2012). Mitochondrial toxicity is also a well-known characteristic of these four drugs (Hynes et al, 2013;Pessayre et al, 2012). Given that patients with hepatocellular jaundice exhibit higher fatality rates than those who do not experience jaundice (Fontana, 2008;Navarro and Senior, 2006), compounds with dual toxicity aspects (i.e., direct hepatocyte death and inhibition of BC network formation) might have a higher risk of fatal DILI than compounds with only one of these two characteristics.…”

“…Thus, a decrease in ATP content was likely not involved in the inhibition of BC network formation in general, at least in our experimental conditions. It is notable that amiodarone, flutamide, benzbromarone, and troglitazone are well-known hepatotoxic drugs, as previously demonstrated in other conventional hepatocyte toxicity assays (Hynes et al, 2013;Kaufmann et al, 2005;Tolosa et al, 2012). Mitochondrial toxicity is also a well-known characteristic of these four drugs (Hynes et al, 2013;Pessayre et al, 2012).…”