Abstract
Abstract: :
Purpose: To test the hypothesis that cataracts induced by U18666A are the result of direct effects of the drug on lens membrane structure rather than inhibition of sterol synthesis. The goals of this study were to describe the distribution of U18666A in biological membranes and its effects on membrane structure and molecular organization. Methods: U18666A was incorporated into membrane vesicles prepared from synthetic phospholipids and bovine lens phospholipids at drug-to-phospholipid mole ratios of up to 1:30. Membrane vesicles were oriented by centrifugation and analyzed using small angle x-ray scattering approaches. Coherent x-ray scattering data were collected on an electronic, position-sensitive detector and integrated using Fourier transform analysis to calculate changes in membrane electron density. The effect of U18666A on membrane structural order or fluidity was measured using the fluorescent probes, NBD-PE and DPH-PC, which partition into the polar head group region and acyl chain region of the membrane lipid bilayer, respectively. Results: X-ray scattering analysis demonstrated that U18666A intercalated into the hydrocarbon core region of both model membrane and bovine lens phospholipid bilayers, as defined by an increase in relative electron density in this region. U18666A also increased the anisotropy (i.e., decreased the fluidity) of NBD-PE and DPH-PC in these membranes, indicating a condensing effect in the hydrocarbon core region of the membrane bilayer as well as in the phospholipid head group region. Conclusion: U18666A intercalates into the center of the lens membrane lipid bilayer and produces a broad increase in membrane structural order. We speculate that these effects could markedly alter membrane permeability and functional properties.
Keywords: 338 cataract • 458 lipids • 390 drug toxicity/drug effects