ROLE OF SMALL GTP-BINDING PROTEINS IN LOVASTATIN-INDUCED CATARACTS

Purpose. To investigate the biochemical mechanisms involved in the cat aract induced by lovastatin, a commonly used cholesterol-lowering agen t. Methods. The effects of lovastatin on lens transparency and on lens epithelial cell proliferation and structure have been investigated us ing organ-cultured rat lenses and cultured epithelial cells from human and rabbit lenses, respectively. Lens histologic and morphologic chan ges were recorded microscopically. Small GTP-binding protein profiles were determined by [alpha-P-32] GTP overlay assays. Results. Rat lense s organ cultured for 7 days with lovastatin, a 3-hydroxy-3-methylgluta ryl CoA reductase inhibitor, developed frank subcapsular opacity. Lens epithelial cells (both human and rabbit) demonstrated extensive morph ologic changes and inhibition of proliferation when treated with lovas tatin. Histologic sections of lovastatin-treated lenses showed partial to complete degeneration of the central epithelium, distortion of elo ngating epithelial cells, and extensive vacuole formation in the equat orial regions of the cortex. Supplementation of the medium with DL-mev alonic acid (a precursor of isoprenoids whose synthesis is inhibited b y lovastatin) prevented the lovastatin-induced changes in whole lenses or in lens epithelial cell cultures, whereas supplementation with cho lesterol had no such effect. GTP-binding proteins accumulated in the s oluble fi-actions of lovastatin-treated lens epithelial cells. This wa s consistent with a blockade in isoprenylation preventing normal assoc iation with membranes. Conclusions. The findings suggest that impairme nt of the function of small GTP-binding proteins, due to a lovastatin- induced blockade in their isoprenylation, affects lens cell structure and proliferation in tissue culture and induces lens opacity in organ culture. These findings are consistent with the proposed roles of smal l GTP-binding proteins as molecular switches that regulate fundamental cellular processes, including growth, differentiation, and maintenanc e of cell structure.