Interactions between non-steroidal anti-inflammatory drugs and biological membranes—I: High amplitude pseudo-energized mitochondrial swelling and membrane permeability changes induced by various non-steroidal anti-inflammatory drugs

Abstract

The action of various non-steroidal anti-inflammatory drugs (NSAID) that are also potent uncoupling agents for oxidative phosphorylation has been studied by measuring light scattering by rat liver mitochondria in different media. These drugs all induce a pseudo-energized high amplitude swelling, except gold salts and salicylates. The amplitude of this swelling is not very dependent on the concentration of the drugs, but the rapidity of the swelling is closely concentration-dependent. Swelling can be induced even with gold salts if p-chloromercuribenzoate ( p-CMB) or Mersalyl is present in the medium, and the rate of swelling initiated by the other NSAID is considerably enhanced. Iodoacetamide and N-ethylmaleimide could not replace p-CMB or Mersalyl in this respect. This difference is probably related to the fact that when the first two thiol inhibitors bind to the mitochondrial membrane, they increase the anionic charges on this membrane. These data also show the importance of thiol groups for the NSAID-induced swelling. This swelling is pseudo-energized (i.e. appears without any substrate), which suggests that the phenomenon is related only to the physieo-chemical changes induced in the membrane by the drugs. This phenomenon is critically affected by the ionic composition of the medium, and a monovalent cationic as well as an anionic selectivity has been found for it. This selectivity can be explained by way of electrostatic forces and gives information on the structure of the membrane, mainly the possible presence of highly polarizable groups. These results suggest that the overall effect of NSAID on mitochondrial metabolism might be related to their activities on ion transport across the mitochondrial membrane.