May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Are All Oxidosqualene Cyclase Inhibitors Cataractogenic?
Author Affiliations & Notes
  • P.S. Sexton
    Biochemistry, Kirksville Coll of Osteopathic Med, Kirksville, MO, United States
  • A.R. Neely
    Biochemistry, Kirksville Coll of Osteopathic Med, Kirksville, MO, United States
  • A.K. Samadi
    Biochemistry, Kirksville Coll of Osteopathic Med, Kirksville, MO, United States
  • J.R. Kuszak
    Ophthalmology/Pathology, Rush-Pres St Lukes Med Ctr, Chicago, IL, United States
  • R.J. Cenedella
    Ophthalmology/Pathology, Rush-Pres St Lukes Med Ctr, Chicago, IL, United States
  • Footnotes
    Commercial Relationships  P.S. Sexton, None; A.R. Neely, None; A.K. Samadi, None; J.R. Kuszak, None; R.J. Cenedella, Roche Pharmaceuticals C, R.
  • Footnotes
    Support  NIH Grant EYO2568 (RJC); EYO6642 (JRK)
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 3490. doi:
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      P.S. Sexton, A.R. Neely, A.K. Samadi, J.R. Kuszak, R.J. Cenedella; Are All Oxidosqualene Cyclase Inhibitors Cataractogenic? . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3490.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: To test whether inhibitors of oxidosqualene cyclase (OSC), besides U18666A, induce cataracts in rats and to probe the mechanism of the cataract. OSC, a sterol synthesis enzyme located in the middle of the pathway, is a target for a "new" generation of blood cholesterol lowering drugs. We hypothesize that the cataract may be partially due to toxicity of accumulated 2,3-monoexpoxysqualene (MES), the substrate of the inhibited enzyme. Methods: Young rats (20 days old) were fed chow containing 0.035% U18666A, 0.10% Ro48-8071 or 0.10% Ro61-0842, all OSC inhibitors. The capacity of these drugs to inhibit growth and sterol synthesis of cultured bovine lens epithelial cells (BLEC), in the presence and absence of added cholesterol, was examined. Liver, serum and lens levels of MES were measured by HPLC after giving U18666A. The capacity of pure MES to inhibit cultured BLEC growth and induce apoptosis was tested. Results: All of the OSC inhibitors induced cataracts within 3-5 weeks of treatment. U18666A was about 5 times and 25 times more potent than Ro48-8071 and Ro61-0842, respectively, in inhibiting cultured BLEC growth. Above a certain concentration, about 40 nM for U18666A, 200 nM for Ro48-8071 and 1000 nM for Ro61-0842, all drugs produced net lens cell kill. Cholesterol added to the culture media reversed the inhibition of cell growth seen at lower drug levels but not cell kill seen at higher levels. MES at over 50 times the level found in lens of U18666A treated rats had no effect on BLEC growth or apoptosis. Conclusions: All tested OSC inhibitors were cataractogenic in rats. The cataract appears not to be due to MES toxicity. The inability of cholesterol to prevent net kill of BLEC suggests that the cataract could be partially due to drug effects independent of the sterol pathway, such as direct perturbation of lens membrane structure.

Keywords: cataract • cell death/apoptosis • lipids 
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