Effects of Ring Substituents on the Activity of Phenols as Inhibitors and Uncouplers of Mitochondrial Respiration

The effects of substituents on the activity of phenols as uncouplers and inhibitors of mitochondrial respiration have been examined. These activities have been correlated with constants describing the effects of the substituents on the electronic and hydrophobic‐bonding properties of the phenol. The coefficients in these correlation equations have been compared with each other and with the coefficients in similar correlations for the effects of phenols on the solubilised ATPase from mitochondria, and their activity in mediating proton conduction across artificial lipid membranes and as inhibitors of a variety of enzymes. Differences in the coefficients in the correlation equations for uncoupling and inhibition of respiration indicate that these depend on different properties of the phenol and hence that they are separate effects and that inhibition of substrate accumulation is not a satisfactory explanation for the inhibition of respiration. High concentrations of uncouplers induce swelling of mitochondria. In the case of 2,4‐dibromophenol, or dicoumarol, this occurs at concentrations similar to those producing inhibition of respiration. With other phenols inhibition of respiration is observed at concentrations lower than those required to induce swelling. The observations reported here support the hypothesis that phenols uncouple by mediating proton conduction across the inner mitochondrial membrane and that, in general, the inhibition of respiration by high concentrations of phenols is due to direct action on a protein component of the respiratory chain.