In VitroInteraction of Nonsteroidal Anti-inflammatory Drugs on Oxidative Phosphorylation of Rat Kidney Mitochondria: Respiration and ATP Synthesis
ABSTRACT Thein vitrointerference of some of most important nonsteroidal anti-inflammatory drugs (NSAIDs) with the respiration of rat kidney (renal cortex) mitochondria and ATP synthesis was evaluated. Acetylsalicylic acid, diclofenac sodium, mefenamic acid, and piroxicam both uncoupled and inhibited oxidative phosphorylation in mitochondria energized with glutamate plus malate or with succinate, while dipyrone only uncoupled and paracetamol only inhibited it. The drug concentrations affecting mitochondrial respiration were in the low to middle micromolar range for diclofenac, mefenamic acid, and piroxicam, and in the low millimolar range for acetylsalicylic acid, dipyrone, and paracetamol. The pattern of inhibition, except for the paracetamol, was similar to that expressed by the respiratory chain inhibitors. NSAIDs also inhibited the rate of ATP synthesis in mitochondria energized with glutamate plus malate, as well as the phosphorylation potential of mitochondria. The IC50values for rate of ATP synthesis, using 2 mMADP, were about 0.1 mMfor diclofenac sodium and mefenamic acid, 0.7 mMfor piroxicam, and in the range of 5–8 mMfor acetylsalicylic acid, dipyrone, and paracetamol. The potential for renal energetic cytotoxicity of NSAIDs is discussed considering their ability to interact with the oxidative phosphorylation in rat renal cortex mitochondria. A comparison is made with the interference of salicylate, the main metabolite of acetylsalicylic acid, and a classical uncoupler of oxidative phosphorylation.
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ABSTRACT: Uncoupling of isolated mitochondria by nonsteroidal antiinflammatory drugs (NSAIDs) has been considered relevant to the development of gastrointestinal (GI) side effects. We investigated the occurrence of NSAID-induced uncoupling of mitochondria in intact cells (rat thymocytes) compared with the effects of a selective cyclooxygenase 2 (COX-2) inhibitor. Oxygen consumption and mitochondrial membrane potential were simultaneously measured amperometrically and by distribution of radioactive tracer molecules, respectively, in the presence and absence of pharmacologically relevant concentrations of the NSAIDs indomethacin and diclofenac and the selective COX-2 inhibitor SC-236. Analysis of data by a technique related to top-down elasticity analysis permitted assessment of the influence of these compounds on individual components of cellular energy metabolism. Indomethacin, diclofenac, and SC-236 increased proton leak in isolated mitochondria. Both diclofenac and SC-236 significantly stimulated proton leak in intact cells and simultaneously inhibited substrate oxidation and ATP turnover. Oxygen consumption rates of isolated cells remained unchanged over a wide concentration range of the drugs, despite significant effects on subsystems of cellular energy metabolism. NSAIDs and selective COX-2 inhibitors have significant and equally directed effects on cellular energy metabolism. They both uncouple mitochondrial respiration and inhibit substrate oxidation and ATP turnover. However, the topical effect and selective COX-2 inhibition may not be sufficient to cause NSAID-like damage to the GI tract.Arthritis & Rheumatology 06/2003; 48(5):1438-44. · 7.48 Impact Factor