Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor
| Autor: | Patricia S. Sexton, Douglas Borchman, Robert F. Jacob, R. Preston Mason, Abbas Samadi, Richard J. Cenedella, Amanda R. Neely, Daxin Tang |
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| Rok vydání: | 2004 |
| Předmět: |
Membrane lipids
Cell anisotropy QD415-436 Biology Biochemistry Cataract Epithelium Phase Transition law.invention Rats Sprague-Dawley Membrane Lipids Mice chemistry.chemical_compound Endocrinology Cataracts law Lens Crystalline medicine Animals Enzyme Inhibitors lens membrane lipids Intramolecular Transferases Cells Cultured Cholesterol apoptosis Membrane structure cholesterol Cell Biology medicine.disease Rats Lens (optics) medicine.anatomical_structure Membrane x-ray diffraction chemistry Apoptosis Biophysics Androstenes Cattle |
| Zdroj: | Journal of Lipid Research, Vol 45, Iss 7, Pp 1232-1241 (2004) |
| ISSN: | 0022-2275 |
| DOI: | 10.1194/jlr.m300469-jlr200 |
| Popis: | Induction of cataracts in experimental animals is a common toxic feature of oxidosqualene cyclase (OSC) inhibitors. U18666A has been shown to produce irreversible lens damage within a few weeks of treatment. Drug actions, besides reducing the availability of cholesterol, could contribute to cataract formation. Cholesterol added to cultures of lens epithelial cells could only partially overcome the growth-inhibiting effects of U18666A. In view of this finding and the fact that U18666A and other OSC inhibitors are highly lipophilic cationic tertiary amines, we tested the hypothesis that the cataractogenic effect of U18666A is related to direct perturbation of lens membrane structure and function. Based on changes in the anisotropy of fluorescent probes, U18666A incorporated into bovine lens lipid model membranes increased membrane structural order and, using small-angle x-ray diffraction, U18666A was shown to intercalate into the lens lipid model membranes and produce a broad condensing effect on membrane structure. Also, exposure of cultured lens epithelial cells and intact rat lenses to U18666A induced apoptosis. Induction of apoptosis may begin by intercalation of U18666A into cell membranes. By increasing membrane structural order, U18666A may also increase light scatter, thus directly contributing to lens opacification. |
| Databáze: | OpenAIRE |
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