抄録
It has recently been said that many of the drugs with FDA Black Box Warning for hepatotoxicity or cardiovascular toxicity are associated with mitochondrial toxicity. Since the dominant function of mitochondria is the production of >90% of the cell’s energy in form of ATP, mitochondrial dysfunction is often involved in the onset of toxicities in the organs that are susceptible to the adverse effect of energy production, such as CNS organs, heart, skeletal muscle and liver. In an attempt to evaluate mitochondrial toxicity in vitro, we adopted following two assay systems:
1. Cytotoxicity assay using HEPG2 cells cultured with media where glucose is replaced by galactose (ie, experimental condition where cells are highly sensitive to mitochondrial toxicity)
2. Energy metabolic assay which affords simultaneous measurement of mitochondrial energy production and cytoplasmic glycolysis using Bio Flux Analyzer XF24 (Seahorse Bioscience Inc).
As a first step, using these assay systems, we evaluated 29 drugs and compounds for which the association of mitochondrial toxicity is suggested. The results showed that (1) both assay systems are very sensitive in detecting mitochondrial toxicity and (2) mitochondrial toxicants with the mechanism of uncoupling activity can be detected by the bio-flux (XF24) assay only. As a next step, we evaluated Astellas compounds associated with hepatotoxicity or skeletal muscle toxicity. The results showed that some of the Astellas compounds have potential of mitochondrial toxicity. These results suggest these approaches will be useful drug discovery.
