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.

Toxicity of lithium on isolated heart mitochondria and cardiomyocyte: A justification for its cardiotoxic adverse effect

“…The mitochondrial swelling, as a result of colloidal osmotic effects of solute flux in and out of the mitochondrial matrix, was measured by monitoring the absorbance at 540 nm (A 540 ) as described by Salimi et al . Briefly, after incubating mitochondrial suspensions with Li + (0, 75, 125, 250, and 500 μM) at 30°C for 5 min in swelling buffer (70 mM sucrose, 230 mM mannitol, 3 mM HEPES, 2 mM tris‐phosphate, 5 mM succinate, and 1 μM of rotenone), the absorbance was measured at 540 nm for 60 min with an ELISA reader (Tecan).…”

Mitochondrial dysfunction and potential anticancer therapy

“…One of its forms, mTORC1, governs mitochondrial biogenesis and mitochondrial activation by eukaryotic initiation factor 4E‐binding protein (4E‐BP) regulation . Sirtuins (SIRTs), a protein family with either mono‐ADP‐ribosyltransferase or deacylase activity, are involved in a wide range of cellular processes like aging, cancer, apoptosis, inflammation, and stress resistance . Several sirtuin members (SIRT3, SIRT4, and SIRT5) found in mitochondria control mitochondrial biogenesis.…”

“…91 Sirtuins (SIRTs), a protein family with either mono-ADP-ribosyltransferase or deacylase activity, are involved in a wide range of cellular processes like aging, cancer, apoptosis, inflammation, and stress resistance. 92 Several sirtuin members (SIRT3, SIRT4, and SIRT5) found in mitochondria control mitochondrial biogenesis. The mTOR pathway increases glutamine metabolism and boots proliferation by inhibiting SIRT4 at transcriptional level.…”

Selective toxicity of persian gulf sea cucumber holothuria parva on human chronic lymphocytic leukemia b lymphocytes by direct mitochondrial targeting

“…The optical density was read at 580 nm wavelength in an ELISA plate reader after 30‐min incubation of the plates with MTT in an incubator. All determinations were confirmed using replication from at least three identical experiments (Pourahmad et al, ; Salimi et al, ).…”