The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

摘要: Dronedarone is used to treat patients with cardiac arrhythmias and has been reported be associated liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes the cytotoxicity of dronedarone. In this study, we examined further underlying mechanisms found after a 24-h treatment HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression topoisomerase II, damage in concentration-dependent manner. We also investigated role cytochrome P450s (CYPs)-mediated metabolism dronedarone-induced toxicity using our previously established lines expressing individually 14 human CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7). CYP3A4, 2D6 were major enzymes metabolize dronedarone, CYP3A7, 1A1, 2B6 but lesser extent. data showed was decreased CYP3A4-, 3A5-, or 2D6-overexpressing cells compared control indicating parent higher potency than metabolites induce these cells. contrast, increased CYP1A1-overexpressing demonstrating CYP1A1 exerts an opposite effect dronedarone's toxicity, comparing 2D6. studied involvement II overexpression increase viability decrease γ-H2A.X induction, suggesting may one involved toxicity.