Effects of long-term administration of HMG-CoA reductase inhibitors on cholesterol synthesis in lens.

The effects of long-term dosing with inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase on the rate of cholesterol biosynthesis were examined in the lens and liver of rats and hamsters. While both pravastatin and lovastatin inhibited incorporation of [14C]acetate into cholesterol in liver slices 2-4 hr after an oral dose, lovastatin, but not pravastatin, inhibited sterol synthesis in lens as well. At 24 hr after a single oral dose, cholesterol synthesis in livers from drug-treated animals was increased compared to controls. This induction of the cholesterol synthetic pathway was observed for both drugs in the liver but only for lovastatin in the lens. After 4 days of once-daily oral doses, synthesis in the lens was induced two to threefold by lovastatin but not by pravastatin. When the drug was included in the continuous diet for 4-5 days, lovastatin caused increases in cholesterol synthesis in the lens whereas lenses from pravastatin-treated animals were identical to controls. This was not a species-specific effect since a similar tissue selectivity was observed in the hamster. The increase in cholesterol synthesis in lenses observed in lovastatin-treated rats was accompanied by an increase in the activity of HMG-CoA reductase enzyme. These studies demonstrate that non-selective HMG-CoA reductase enzyme inhibitors can inhibit cholesterol synthesis in the lens, and following this inhibition a marked induction in the cholesterol biosynthetic pathway develops in the lens and this induction is associated with an increase in HMG-CoA reductase enzyme activity.