Role of respiratory uncoupling in drug-induced mitochondrial permeability transition

Mitochondrial injury contributes to severe drug-induced liver injury. Particularly, mitochondrial permeability transition (MPT) is thought be relevant cytolytic hepatitis. However, the mechanism of MPT unclear and prediction not adequately evaluated in preclinical stage. In a previous study, we found that troglitazone, drug withdrawn due injury, induced via mild depolarization probably resulting from uncoupling. Herein, investigated whether other drugs induce share similar properties as using isolated mitochondria rat liver. Of 22 test examined, six drugs, including showed an uncoupling effect. Additionally, receiver operating characteristic analysis was conducted predict potential respiratory control ratio, indicator intensity. Results 2.5 best threshold exhibited high sensitivity (1.00) specificity (0.81), indicating correlated with potential. Activation calcium-independent phospholipase A2 appeared involved uncoupling-induced MPT. Furthermore, strong relationship between intensity effect among compounds confirmed. These results may help predicting cultured cells modifying chemical structures reduce risk. • The correlates Uncoupling induces iPLA 2 activation. Structure-activity for applicable