Troglitazone induces a rapid drop of mitochondrial membrane potential in liver HepG2 cells

Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

“…47 Oxidative stress can activate aged rodents 55 and in other models of mitochondrial injury, 56 and is considered a marker of mitochondrial toxicity. 57,58 Furthermore, AMA decreased cell viability and activated apoptotic markers, as well as inhibited cellular respiration in cardiomyocytes, further increasing cytotoxicity (Fig.…”

Troglitazone Stimulates Cancer Cell Uptake of 18F-FDG by Suppressing Mitochondrial Respiration and Augments Sensitivity to Glucose Restriction

“…Emerging evidence points to the ability of troglitazone to directly and indirectly influence mitochondrial function (6)(7)(8)(9). Increased lactate production in our study points to a glycolytic shift of metabolism that may reflect an effort to maintain sufficient energy for function and survival in the face of reduced mitochondrial function.…”

“…The influence of troglitazone on mitochondrial function includes disruption of MMP, as has been observed in hepatocyte-derived cancer cells within an hour at concentrations considered therapeutically active (8,21). This observation may indicate a contribution of suppressed oxidative metabolism to the hepatotoxic effect of troglitazone.…”

“…Although the precise mechanisms for such actions have yet to be clarified, a role for direct influence on mitochondrial function has been proposed (6). Mitochondrial dysfunction has been implicated in the hepatotoxic side effect of troglitazone by observations of a rapid drop of mitochondrial membrane potential (MMP) in isolated hepatocytes (7) and hepatic cancer-derived cells exposed to the drug (8). In a more recent study, troglitazone was observed to also induce an acute reduction of MMP in breast cancer cells (9).…”

Mitochondria as a Biosensor for Drug-induced Toxicity – Is It Really Relevant?

“…An example of TZD which had high impact in the clinic is troglitazone (TRO), introduced in 1997 but soon withdrawn from the market because of reports of serious hepatotoxicity, receiving a black box warning from the U.S. Food and Drug Administration (FDA). In fact, TRO, when incubated with HepG2 cells, decreased cellular ATP and  (Tirmenstein, Hu et al, 2002;Bova, Tam et al, 2005). Lim et al also demonstrated that TRO increases intramitochondrial oxidative stress that activates the Trx2/Ask1 pathway, leading to mitochondrial permeabilization (Lim, Liu et al, 2008).…”