Effect of N-Phenylanthranilic Acid Scaffold Nonsteroidal Anti-inflammatory Drugs on the Mitochondrial Permeability Transition.

Hepatotoxicity is a known side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, the effects of N-phenylanthranilic acid (NPA) scaffold NSAIDs on rat liver mitochondria were examined. Mefenamic acid (MEF, 200 µM) induced mitochondrial swelling, which was inorganic phosphate (Pi)-dependent and suppressed by cyclosporin A (CsA, 2.5 µM), similar to calcium-induced swelling. Mitochondrial swelling was also observed following the addition of 200 µM flufenamic acid (FLU), meclofenamic acid (MCL), and tolfenamic acid (TOL). Less swelling was observed with the addition of 200 µM diclofenac (DIC) or NPA. Diphenylamine (DPA)-induced swelling occurred in a Pi-independent manner and was not sensitive to CsA. The mechanism by which DPA interacted with the mitochondrial inner membrane differed from those of the other NPA scaffold NSAIDs. The addition of 50 µM MEF, MCL, TOL, and FLU had uncoupling effects in mitochondrial inner membrane. These NSAIDs dose-dependently obstructed electron transport in the respiratory chain. NSAIDs are known to have various dynamic structures, and the solvation free energies (dGWs: an index of stereo-hydrophobicity) of the conformers obtained were determined using a molecular orbital analysis. The relationship between the dynamic structures and swelling induced by NPA scaffold NSAIDs was also examined.