In vitro interaction of nonsteroidal anti-inflammatory drugs on oxidative phosphorylation of rat kidney mitochondria: respiration and ATP synthesis.
The in vitro interference 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 IC50 values for rate of ATP synthesis, using 2 mM ADP, were about 0.1 mM for diclofenac sodium and mefenamic acid, 0.7 mM for piroxicam, and in the range of 5-8 mM for 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.
Department of Physics and Chemistry, University of Sõ Paulo, RibeirãoPreto, Brazil.
F E
FE
Mingatto
A C
AC
Santos
S A
SA
Uyemura
M C
MC
Jordani
C
C
Curti
D000082:Acetaminophen / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004177:Dipyrone / Q000494:pharmacology; D007672:Kidney Cortex / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010894:Piroxicam / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014475:Uncoupling Agents / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014475:Uncoupling Agents; D010894:Piroxicam; D004008:Diclofenac; D000082:Acetaminophen; D008528:Mefenamic Acid; D004177:Dipyrone; D000255:Adenosine Triphosphate; D001241:Aspirin