J. Lipid Res.
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A more recent version of this article appeared on January 1, 2003

Papers In Press, published online ahead of print November 4, 2002
J. Lipid Res., doi:10.1194/jlr.M200002-JLR200
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Submitted on January 3, 2002
Revised on October 16, 2002
Accepted on October 16, 2002

Discordant expression of the sterol pathway in lens underlies simvastatin induced cataracts in Chbb:Thom rats

Richard J. Cenedella, Jerome R. Kuszak, Kristin J. Al-Ghoul, Shucun Qin, and Patricia S. Sexton

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

Corresponding Author: rcenedella{at}kcom.edu

Abstract Simvastatin rapidly induced cataracts in young Chbb:Thom (CT) but not Sprague Dawley (SD) or Hilltop Wistar (HW) rats. Oral treatment for 14 but not 7 days committed CT rat lenses to cataract formation. The cholesterol to phospholipid molar ratio in lenses of treated CT rats was unchanged. Differences between strains in serum and ocular humor levels of simvastatin acid poorly correlated with susceptibility to cataracts. No significant differences were found between rat strains in the capacity of simvastatin acid to inhibit lens-basal sterol synthesis. Prolonged treatment with simvastatin comparably elevated HMG CoA reductase protein and enzyme activity in lenses of both cataract resistant and sensitive strains. However, in contrast to SD and HW rats, where sterol synthesis was markedly increased, sterol synthesis in CT rat lenses remained at baseline. Discordant expression of sterol synthesis in CT rats may be due to inadequate upregulation of lens HMG CoA synthase. HMG CoA synthase protein levels , and to a much lesser extent mRNA levels, increased in lens cortex of SD but not CT rats. Because up-regulation of the sterol pathway may result in increased formation of isoprene-derived anti-inflammatory substances, failure to up-regulate the pathway in CT rat lenses may reflect an attenuated compensatory response to injury that resulted in cataracts.


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