The effects of hexachlorophene on mitochondrial and artificial membrane systems Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/m326m4721

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  • Hexachlorophene (HCP; 2,2'-methylenebis-(3,4,6-trichlorophenol)) was developed as an antibacterial agent but was also found to induce toxic effects in various tissues in animals and humans. Changes were found in myelinated nerve fibers and cerebral white matter. Erythrocytes are hemolysed in vitro. Oxidative phosphorylation is uncoupled by HCP at concentrations less than 1.0 nmoles per mg of mitochondrial protein. The work in this thesis was designed to investigate the effects of HCP on mitochondrial membranes, lipid vesicles, and lipid bilayer membranes and their relation to the above toxic effects. HCP was found to bind to sonicated lecithin vesicles as if bound in a hydrophobic environment as demonstrated by UV difference spectroscopy. The binding sites were independent and numbered about one site for every fifteen lecithin molecules. The binding of ¹⁴ C-HCP to rat liver mitochondria was different in that it showed positive cooperativity at concentrations of HCP below a few nmoies per mg of mitochondria' protein. The cooperativity was altered by the presence of pyruvate. Even though the binding may be predominantly to protein sites, the cooperativity may reflect changes in the electrical gradient across the mitochondrial membrane. Electron microscopy showed that HCP induced a change in configuration of the mitochondria from the condensed to the orthodox congifuration. The change was dependent on a functional electron transport chain. There was also an apparent expansion of the inner membrane. HCP caused an increase in the electrical conductivity of lipid bilayer membranes made from lecithin and other phospholipids. This increase was due to an increase in permeability to hydrogen ions without an increase in permeability to potassium ions or physical disruption of the lipid bilayers. The mechanism appears to involve the HCP monoanion as the charge carrier. A study of rat liver mitochondrial permeability to protons was analyzed by the compartmental method and showed the presence of a mitochondrial compartment, representing mitochondria bounded by the inner membrane, and an extramitochondrial compartment. The buffering capacity and membrane permeability of the compartments was measured. HCP increased the permeability of the inner membrane to protons, and pH and temperature studies showed that the mechanism involves the transference of the HCP monoanion across the membrane. These effects occurred at concentrations of HCP below those needed to uncouple oxidative phosphorylation. HCP increased the fluidity and motion of stearic acid and cholesterol spin labels in both lipid vesicles and rat liver mitochondria. HCP induced an increase in accessibility of the stearic acid spin label to hydrogen bonding.
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