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A more recent version of this article appeared on July 1, 2004

Papers In Press, published online ahead of print April 21, 2004
J. Lipid Res., doi:10.1194/jlr.M300469-JLR200
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Submitted on November 12, 2003
Revised on April 20, 2004
Accepted on April 21, 2004

Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor

Richard J. Cenedella, Robert Jacob, Douglas Borchman, Daxin Tang, Amanda R. Neely, Abbas Samadi, R. Preston Mason, and Patricia S. Sexton

Department of Biochemistry, Kirksville College of Osteopathic Medicine, Kirksville, MO 63501

Corresponding Author: rcenedella{at}atsu.edu

Abstract Inhibitors of oxidosqualene cyclase, a central enzyme in the sterol synthesis pathway, are being investigated as a potential new generation of hypocholesterolemic drugs. Induction of cataracts in experimental animals is a common toxic feature of these agents. U18666A is an oxidosqualene cyclase inhibitor that has been widely studied and 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 findings and the fact that U18666A and other oxidosqualene cyclase 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 rather than to decreased availability of cholesterol. 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. Apoptosis may underlie many cataracts. We propose that induction of apoptosis may begin by intercalation of U18666A into cell membranes. By increasing membrane structural order, U18666A may also increase light scatter in the lens, thus directly contributing to lens opacification.


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