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.
Kalinowski
S S
SS
Bristol-Myers Squibb Institute for Pharmaceutical Research, Department of Metabolic Diseases, Princeton, NJ 08543.
Tanaka
R D
RD
Mosley
S T
ST
D000085:Acetates / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007908:Lens, Crystalline / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D019821:Simvastatin; D013997:Time Factors
D000085:Acetates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin