DNA damage‐induced apoptosis and mitogen‐activated protein kinase pathway contribute to the toxicity of dronedarone in hepatic cells

Abstract

Dronedarone, an antiarrhythmic drug, has been marketed as an alternative to amiodarone. The use of dronedarone has been associated with severe liver injury; however, the mechanisms remain unclear. In this study, the possible mechanisms of dronedarone induced liver toxicity were characterized in HepG2 cells. Dronedarone decreased cells viability and induced apoptosis and DNA damage in a concentration- and time-dependent manner. Pretreatment of the HepG2 cells with apoptosis inhibitors (caspase-3, -8, and -9) or the necrosis inhibitor (Necrox-5), partially, but significantly, reduced the release of lactate dehydrogenase. Dronedarone caused the release of cytochrome c from mitochondria to cytosol, a prominent feature of apoptosis. In addition, the activation of caspase-2 was involved in dronedarone induced DNA damage and the activation of JNK and p38 signaling pathways. Inhibition of JNK and p38 by specific inhibitors attenuated dronedarone-induced cell death, apoptosis, and DNA damage. Additionally, suppression of caspase-2 decreased the activities of JNK and p38. Dronedarone triggered DNA damage was regulated by downregulation of topoisomerase IIα at both transcriptional and post-transcriptional levels. Taken together, our data show that DNA damage, apoptosis, and the activation of JNK and p38 contribute to dronedarone-induced cytotoxicity. Environ. Mol. Mutagen. 59:278-289, 2018. © 2018 Wiley Periodicals, Inc.

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

“…Our previous study investigated dronedarone-induced toxicity after 6 h treatment and demonstrated that there was significant cytotoxicity when cells were treated with drone-darone at 10 μM for 6 h (Chen et al 2018). It has been reported that dronedarone can be detected within 24 h incubation in metabolically competent human primary hepatocytes (Klieber et al 2014).…”

“…Significant cytotoxicity was observed in both cell lines, but HepG2 cells displayed a higher sensitivity to dronedarone than the metabolically competent HepaRG cells (Chen et al 2018). These results stimulated the current investigation to determine which drug-metabolizing enzymes are most important in the toxicity or detoxification of dronedarone, i.e., whether they enhance or reduce its toxicity.…”

“…Our previous study on dronedarone-induced cytotoxicity revealed that the suppression of topoisomerase IIα might be a potential mechanism for DNA damage (Chen et al 2018). In this study, we further studied the role of topoisomerase IIα in the toxicity of dronedarone by overex-pressing topoisomerase IIα in HepG2 cells.…”

“…Since dronedarone is still in use and reports of hepatotoxicity continue (Rizkallah et al 2016), evaluating the toxicity of dronedarone and studying its underlying mechanisms are an urgent priority. Thus far, only a few studies has investigated the mechanisms of dronedarone-induced toxicity, with mitochondrial dysfunction (Felser et al 2013, 2014; Serviddio et al 2011) and DNA damage-induced apoptosis (Chen et al 2018) being reported.…”

“…In addition, the mechanisms underlying dronedarone-induced toxicity were investigated after a 24 h exposure of dronedarone to cells at clinically relevant concentrations. Since we previously demonstrated that a 4-h treatment of dronedarone could induce DNA damage and topoisomerase II suppression in HepG2 cells (Chen et al 2018), we further studied the direct involvement of topoisomerase II in dronedarone-induced DNA damage by over-expressing the topoisomerase II gene. Furthermore, we extensively examined the roles of human CYP isoforms in dronedarone-induced liver toxicity.…”