Intense and Intensified Electric Fields in the Low-Permittivity Interior of the Biological Membrane — Nanoscale Reactor for Hydroxyl Radical Formation

An electric field applied externally to a biological cell in an aqueous electrolyte medium induces transmembrane voltages by two mechanisms: 1. the polarized orientation of lipid head group and water dipoles; and 2. the migration of mobile charge to the impermeable membrane interface. If the transmembrane potential, Psi_m, reaches values of a few hundred millivolts, permeabilizing structures form in the membrane, and its barrier function is compromised or lost. For pulsed electric fields applied for times longer than a few nanoseconds, the “charging” of the membrane by mobile ions determines the resulting Psi_m. This is the mobile charge realm of “classical” electroporation. For pulsed electric field exposures that are very short (< 10 ns), significant transmembrane potentials can arise from the field-aligned orientation of interfacial water and head group dipoles. This is the dielectric regime of “nanoelectroporation”. In both long and short-pulse cases, peroxidation of membrane lipids has been reported at very early times after the electric field is delivered. The mechanism for this peroxidation has not been identified. We propose that hydroxyl radicals are generated within nanoseconds in the low-permittivity, high-effective-field environment of the electropermeabilizing lipid bilayer interior, and we describe a plausible sequence of events for this process, consistent with known reaction pathways from water to hydroxyl radical, with molecular models for lipid electropore formation, and with experimental observations.