Discordant expression of the sterol pathway in lens underlies simvastatin-induced cataracts in Chbb

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. HMGCoA synthase protein levels, and to a much lesser extent mRNA levels, increased in lens cortex of SD but not CT rats. Because upregulation of the sterol pathway may result in increased formation of isoprene-derived anti-inflammatory substances, failure to upregulate the pathway in CT rat lenses may reflect an attenuated compensatory response to injury that resulted in cataracts.-Cenedella, R. J., J. R. Kuszak, K. J. AlGhoul, S. Qin, and P. S. Sexton. Discordant expression of the sterol pathway in lens underlies simvastatin-induced cataracts in Chbb:Thom rats. J. Lipid Res. 2003. 44: 198-211.

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

“…23,24 Certain drugs that inhibit cholesterol biosynthesis have been shown to induce cataract development in animal models as a result of reducing essential levels of lens membrane cholesterol. [25][26][27] …”

Functional Polymorphisms of the Lss and Fdft1 Genes in Laboratory Rats

“…It would not be unreasonable to presume that rat strains with the Lss S allele would be more susceptible to the cataractogenic effect of U18666A, or even other cholesterol-lowering drugs. Indeed, a specific strain of Wistar rats (Chbb:Thom rats) was highly susceptible to the cataractogenic effects of simvastatin, which inhibits HMG-CoA reductase in the cholesterol biosynthesis pathway [3]. In that case, it was postulated that this rat strain carried a genetic defect in the regulation of a key enzyme downstream of mevalonic acid in the cholesterol biosynthesis pathway that rendered the rats more susceptible to the cataractogenic effects of simvastatin.…”

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

“…WCS alone contains ‫ف‬ 1.3 mg cholesterol/ml. The effects of U18666A on the apoptosis of BLEC and J774 macrophages cultured in medium with whole serum were assessed at various times after drug addition using the DeadEnd Colorimetric Apoptosis Detection System (Promega, Madison, WI) essentially as recently described (9). Using this technique, we additionally examined the capacity of U18666A to induce apoptosis in the epithelial cell layer of intact rat lenses incubated with U18666A and in lenses of rats treated for 2-4 weeks with U18666A (0.035% in chow).…”

“…Pharmacological inhibition of desmosterol reductase (6) or oxidosqualene cyclase (OSC) (7,8) causes cataracts in rodents, and inhibition of HMGCoA reductase by statins can induce cataracts in rats (9) and increase the risk of cataracts in humans (10). Simvastatin was shown to cause rapid lens damage and induce the formation of cataracts in Chbb:Thom rats (9). Simvastatin treatment also tripled the risk of cataracts in humans who concomitantly received two or more courses of erythromycin (10).…”

“…Genetically based deficiencies in mevalonate kinase (2), ⌬ 8, ⌬ 7-sterol isomerase (emapomil binding protein) (3) , 3 ␤ -hydroxysterol ⌬ 7-reductase (4), and 3 ␤ -hydroxysterol ⌬ 24-reductase (5) can result in human cataracts. Pharmacological inhibition of desmosterol reductase (6) or oxidosqualene cyclase (OSC) (7,8) causes cataracts in rodents, and inhibition of HMGCoA reductase by statins can induce cataracts in rats (9) and increase the risk of cataracts in humans (10). Simvastatin was shown to cause rapid lens damage and induce the formation of cataracts in Chbb:Thom rats (9).…”