PESTICIDES AND ION TRANSPORT ACROSS LIPID MEMBRANES

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This project is an in depth study of the forms of permeatoxicity in which pesticides interact with lipid membranes causing changes of permeability to protons, and to lipid soluble ions. The two classes of pesticides which will be investigated are (a) those derived from substituted phenols, which act as protonophores and disrupt energy conversion processes in cells, and (b) those derived from chlorinated phenoxy and benzoic acids, including their metabolic products, which change ionic selectivity of membranes. The major goal of establishing quantitative models of pesticide-membrane interactions will require coordinated studies in three general areas: (1) The first area will be a multifaceted exploration of pesticide adsorption. Determinations will be made of the distribution of both neutral and ionized forms of pesticides between aqueous phases and membranes, lipid monolayers, and organic solvents representative of different membrane regions. These studies will be complemented by investigations of pesticide induced changes of electric potential profiles across organized-lipid/water interfaces, studies of where each form of pesticide is localized in lipid arrays, and measurements of the thermodynamic parameters of pesticide adsorption. The methods employed will include microelectrophoresis of liposomes, measurements of surface potential, determinations of compression isotherms and isobars of lipid monolayers, and observations of gel-fluid transformations in membranes. (2) The second area will focus on the hydrogen-bonded complexes formed between the neutral and ionized molecules of phenol-based pesticides whose presence in membrane is essential for pesticide-mediated proton permeability. Studies will include mesurements of stability constants of complexes in membrane-like solvents and structural determinations on complexes prepared in pure form with various organic counterions. (3) The third area encompasses the elucidation, through steady-state and dynamical membrane conductivity measurements operating in the time and/or frequency domains of the kinetics of pesticide-altered ionic permeability. The kinetic studies of protonophoretic pesticides will rely on the existence of pesticide-induced membrane conductivity, whereas studies of those acting as ion selectivity modifiers will utilize well defined transport schemes set up by membrane ion probes. The combination of results from the above three research areas will provide a basis for a comprehensive understanding of the mechanisms by which many important pesticides interfere with the crucial role of biomembranes as a permeability barrier to charged solutes.