Evaluation of in vitro effects of ifosfamide drug on mitochondrial functions using isolated mitochondria obtained from vital organs.

Abstract

Mitochondrial toxicity has been shown to contribute to a variety of organ toxicities such as, brain, heart, kidney, and liver. Ifosfamide (IFO) as an anticancer drug, is associated with increased risk of neurotoxicity, cardiotoxicity nephrotoxicity, hepatotoxicity, and hemorrhagic cystitis. The aim of this study was to evaluate the direct effect of IFO on isolated mitochondria obtained from the rat brain, heart, kidney, and liver. Mitochondria were isolated with mechanical lysis and differential centrifugation from different organs and treated with various concentrations of IFO. Using biochemical and flowcytometry assays, we evaluated mitochondrial succinate dehydrogenase (SDH) activity, mitochondrial swelling, lipid peroxidation, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP). Our data showed that IFO did not cause deleterious alterations in mitochondrial functions, mitochondrial swelling, lipid peroxidation ROS formation, and MMP collapse in mitochondria isolated from brain, heart, kidney, and liver. Altogether, the data showed that IFO is not directly toxic in mitochondria isolated from brain, heart, kidney, and liver. This study proved that mitochondria alone does not play the main role in the toxicity of IFO, and suggests to reduce the toxicity of this drug, other pathways resulting in the production of toxic metabolites should be considered.