Toxicity of macrolide antibiotics on isolated heart mitochondria: a justification for their cardiotoxic adverse effect

Abstract

1. Macrolides belong to the polyketide class of natural products. These products are a group of drugs (typically antibiotics) which their activity stems from the presence of a macrolide ring. Antibiotic macrolides are used to treat infections caused by Gram-positive bacteria and Haemophilus influenzae infections such as respiratory tract and soft-tissue infections. Macrolides, mainly erythromycin and clarithromycin, rarely show QT prolongation, as their infamous adverse reaction which can lead to torsades de pointes. Electrophysiological studies showed that macrolides prolonging the QT interval inhibit the rapid component of the delayed rectifier K+ current (IKr) through the block of potassium channels encoded by the human ether-a-go-go-related gene (HERG). Other studies suggest that increased ROS generation alters the kinetics of hERG K+ conductance.2. In our study, rat cardiomyocytes were isolated with collagen perfusion technique. Finally, mitochondria isolated from cardiomyocytes were exposed to erythromycin, azithromycin and clarithromycin for their probable toxicity effects.3. Our results demonstrated that macrolides induced reactive oxygen species formation, mitochondrial membrane permeabilization and mitochondrial swelling and finally cytochrome c release in cardiomyocyte mitochondria.4. These findings suggested that the toxicity of heart mitochondria is a starting point for cardiotoxic effects of macrolides including QT prolongation, torsades de pointes and arrhythmia.