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

Article Details

Citation

Cenedella RJ, Kuszak JR, Al-Ghoul KJ, Qin S, Sexton PS

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

J Lipid Res. 2003 Jan;44(1):198-211.

PubMed ID
12518039 [ View in PubMed
]
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 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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Mevastatin3-hydroxy-3-methylglutaryl-coenzyme A reductaseProteinHumans
Yes
Inhibitor
Details
Simvastatin3-hydroxy-3-methylglutaryl-coenzyme A reductaseProteinHumans
Yes
Inhibitor
Details