Diclofenac sodium and mefenamic acid: potent inducers of the membrane permeability transition in renal cortex mitochondria.
The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to induce Ca(2+)-mediated/cyclosporin A-sensitive mitochondrial membrane permeability transition (MMPT) was evaluated by monitoring swelling of isolated rat renal cortex mitochondria in the presence of 20 microM CaCl2. Dipyrone and paracetamol did not induce MMPT, while piroxicam and acetylsalicylic acid (and its metabolite salicylate) were poor inducers. In contrast, diclofenac sodium and mefenamic acid were potent triggering agents, inducing MMPT at 2 microM, a concentration below those previously shown to uncouple and/or inhibit oxidative phosphorylation. When compared to salicylate, a classical uncoupler and inducer of MMPT, the potency of diclofenac sodium and mefenamic acid was about 50-fold greater. Swelling was completely prevented by EGTA, cyclosporin A, or MgCl2, and only partially by ADP or dithiothreitol. Under the same experimental conditions as for the swelling assays, the drugs depressed the membrane potential of mitochondria, an effect prevented by cyclosporin A and restored by EGTA. Also, the drugs did not induce membrane lipid peroxidation or changes in GSSG levels, but led to a small decrease in protein thiol content, as well as to a substantial decrease in the NADPH levels of mitochondria. Hence, membrane depolarization and pyridine nucleotide oxidation seem to be involved in MMPT induction by these NSAIDs. The potency in eliciting the process, like the uncoupling activity, seems to be influenced by the lipophilic character of the molecules.
Uyemura
S A
SA
Department of Clinical, Toxicological, and Bromatological Analysis, School of Pharmaceutical Sciences, University of São Paulo, Brazil.
Santos
A C
AC
Mingatto
F E
FE
Jordani
M C
MC
Curti
C
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology*; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008528:Mefenamic Acid / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010084:Oxidation-Reduction; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology; D020156:Salicylic Acid; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012459:Salicylates; D013438:Sulfhydryl Compounds; D004008:Diclofenac; D008528:Mefenamic Acid; D016572:Cyclosporine; D020156:Salicylic Acid