Kinetic Model To Describe the Intrinsic Uncoupling Activity of Substituted Phenols in Energy Transducing Membranes

A new approach to understand the increased toxicity of uncouplers as compared to baseline toxicity (narcosis) is presented here. The overall uncoupling activity is quantitatively separated into the contribution of membrane concentration and speciation and intrinsic activity. This approach is a further step toward the development of improved Quantitative Structure−Activity Relationships (QSAR) and of toxicokinetic models used in risk assessment. The protonophoric uncoupling activity of seven nitro- and chlorophenols has been investigated as a function of pH and concentration using time-resolved spectroscopy on photosynthetic membranes. The experimental data are described by a kinetic model that includes a monomeric and a dimeric protonophoric shuttle mechanisms. Input parameters of the model are the experimental data for relaxation of the membrane potential, the biomembrane-water distribution constants of the phenol and phenoxide species, and the acidity constant of the phenol. Adjustable parameters are the translocation rate constants of all phenolic species and the heterodimer formation constant. These parameters constitute the intrinsic uncoupling activity. Hydrophobicity and acidity govern the partitioning of phenols into the membrane but appear not to be the sole determining factors for the intrinsic uncoupling activity of phenolic compounds. Additional factors include steric effects and charge distribution within the molecule.