Nonsteroidal antiinflammatory drugs and a selective cyclooxygenase 2 inhibitor uncouple mitochondria in intact cells.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
University Hospital Charité, Humboldt-University Berlin, Berlin, Germany.
Manja M
MM
Krause
Martin D
MD
Brand
Stefan
S
Krauss
Christian
C
Meisel
Hartmut
H
Vergin
Gerd-Rüdiger
GR
Burmester
Frank
F
Buttgereit
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects; D007527:Isoenzymes / Q000009:adverse effects*; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000009:adverse effects*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000096926:Benzenesulfonamides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac; D007213:Indomethacin; D007527:Isoenzymes; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides