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Journal of Lipid Research, Vol. 45, 1232-1241, July 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

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

Richard J. Cenedella^1,*, Robert Jacob, Douglas Borchman, Daxin Tang, Amanda R. Neely^*, Abbas Samadi^*, R. Preston Mason and Patricia Sexton^*

^* Department of Biochemistry, Kirksville College of Osteopathic Medicine, Kirksville, MO 63501
Elucida Research, Beverly, MA 01915
Department of Ophthalmology and Visual Science, University of Louisville, Louisville, KY 40202

¹ To whom correspondence should be addressed. e-mail: rcenedella{at}kcom.edu

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.

Supplementary key words cholesterol • lens membrane lipids • anisotropy • x-ray diffraction • apoptosis

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